No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats
Abstract
Agmatine, a polycationic amine synthesized via decarboxylation of l-arginine by arginine decarboxylase is reported to exhibit anti-hyperglycemic, antioxidant and memory enhancing effects. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze and object recognition paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as a marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with agmatine (5-10mg/kg, i.p. for 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. Further, memory improving effects of agmatine were independent of adrenal I(2) imidazoline receptors. In a separate set, agmatine treatment for an initial 15 days after diabetes confirmation also significantly reduced memory impairment during training trials after 30 days of diabetes confirmation. Moreover, treatment during training trials (30 days after diabetes) also significantly reduced memory impairment in diabetic rats. In conclusion, the present study demonstrates that treatment with agmatine prevents changes in oxidative stress and ChE activity, and probably consequent memory impairment in diabetic rats.
... The experiments were repeated 3 times. BDNF: Brain-derived neurotrophic factor; CREB: cAMP-response element-binding protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; p-CREB: phosphorylated cAMP-response element-binding protein; SIRT1: Sirtuin 1; Sirtinol: SIRT1 inhibitor; SRT2104: SIRT1 activator; STZ: streptozotocin; TORC1: target of rapamycin complex 1. reported in many studies (Bhutada et al., 2012;Ye et al., 2018;Tabassum et al., 2020). For instance, male rats fed with a highfat diet and given a 35 mg/kg STZ injection to induce a type 2 diabetic model showed significant deficits in spatial learning and memory function in the MWM test after 9 weeks (Ye et al., 2018). ...
... For instance, male rats fed with a highfat diet and given a 35 mg/kg STZ injection to induce a type 2 diabetic model showed significant deficits in spatial learning and memory function in the MWM test after 9 weeks (Ye et al., 2018). In another study, a type 1 diabetes mellitus model was induced by a single injection of 60 mg/kg STZ, and these rats exhibited impaired performance in the MWM test and a reduced investigation ratio in the novel object recognition task after 30 days of modeling (Bhutada et al., 2012). The doses of STZ, the method of STZ injection, and the duration of diabetes modeling differ across studies. ...
... In the hidden platform test, the escape latency for rats to find the platform is used to evaluate the learning function of rats. Currently, these data are commonly analyzed by one-way analysis of variance (Vorhees and Williams, 2006;Bhutada et al., 2012;. The one-way analysis of variance is also incorporated into the language of the general linear model (GLM) (Scott et al., 2014). ...
In the peripheral nervous system, the activation of Sirtuin 1 can improve insulin resistance; however, the role played by Sirtuin 1 in the central nervous system remains unknown. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin. At 8 weeks after streptozotocin injection, the Morris water maze test and western blot assays confirmed that the diabetic model rats had learning and memory deficits, insulin resistance, and Sirtuin 1 expression could be detected in the hippocampus. Insulin and the insulin receptor inhibitor S961 were intranasally administered to investigate the regulatory effects of insulin signaling on Sirtuin 1. The results showed that insulin administration improved the impaired cognitive function of diabetic model rats and increased the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1 in the hippocampus. Conversely, S961 administration resulted in more severe cognitive dysfunction and reduced the expression levels of phosphorylated insulin receptor, phosphorylated insulin receptor substrate 1, and Sirtuin 1. The Sirtuin 1 activator SRT2104 and the inhibitor Sirtinol were injected into the lateral ventricle, which revealed that the activation of Sirtuin 1 increased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor. Hippocampal dendritic length and spine density also increased in response to Sirtuin 1 activation. In contrast, Sirtinol decreased the expression levels of target of rapamycin complex 1, phosphorylated cAMP-response element-binding protein, and brain-derived neurotrophic factor and damaged the dendritic structure. These findings suggest that the Sirtuin 1 signaling pathway plays an important role in the development of insulin resistance-related cognitive deficits in diabetic rats. This study was approved by the Animal Ethics Welfare Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine (approval No. ZYFY201811207) in November 2018. © 2021 Wolters Kluwer Medknow Publications. All rights reserved.
... In fact, data from animal models of diabetes indicate that it can both stimulate insulin secretion and enhance cellular sensitivity to insulin (Zhang et al. 2021b). These antihyperglyemic effects of agmatine rely on multiple mechanisms; including modulation of signaling mediated by imidazoline receptors I 2 R and I 3 R (Hwang et al. 2005;Ko et al. 2008;Su et al. 2009;Chang et al. 2010;Tsai et al. 2014;Li et al. 2015), attenuation of hyperglycemia-induced proinflammatory signaling (Ferents et al. 2016;Song et al. 2016;Kim et al. 2016), restoration of redox (Bhutada et al. 2012;Song et al. 2014;Bila et al. 2019) and NOS/NO (Cui et al. 2012;Abo El Gheit et al. 2021) signaling deficits, and rescue of vascular dysfunction (Özyazgan et al. 2003). Further, in addition to stimulating pancreatic β-cells to secrete insulin (Cripps et al. 2020), agmatine also activates insulin-dependent downstream cell survival phosphoinositide 3-kinase/Akt/ glycogen synthase kinase 3 beta (PI3K/Akt/GSK3β) signaling pathway (Moosavi et al. 2014;Kang et al. 2017). ...
... In addition, agmatine elicits robust ameliorative actions against high glucose-induced neuronal damage in animal models of diabetic retinopathy, possibly via its actions on NMDA receptors, and inflammatory and cell survival/death mediators (Han et al. 2015;Song et al. 2016;Abo El Gheit et al. 2021). Importantly, agmatine has been evidenced to ameliorate diabetes-associated neuropsychological symptoms of depression and anxiety (Kale et al. 2020;Kotagale et al. 2021), as well as deficits in learning and memory in animal models (Cui et al. 2012;Bhutada et al. 2012;Song et al. 2014;Moosavi et al. 2014;Kim et al. 2016;Kang et al. 2017). Lastly, clinical trials (Rosenberg et al. 2020) and animal studies (Rondón et al. 2018) also implicate agmatine in abrogation of neuropathic pain associated with diabetes. ...
Purpose
Diabetes mellitus (DM) and epilepsy and the psychological and socio-economic implications that are associated with their treatments can be quite perplexing. Metformin is an antihyperglycemic medication that is used to treat type 2 DM. In addition, metformin elicits protective actions against multiple diseases, including neurodegeneration and epilepsy. Recent studies indicate that metformin alters the resident gut microbiota in favor of species producing agmatine, an arginine metabolite which, in addition to beneficially altering metabolic pathways, is a potent neuroprotectant and neuromodulant.
Methods
We first examine the literature for epidemiological and clinical evidences linking DM and epilepsy. Next, basing our analyses on published literature, we propose the possible complementarity of agmatine and metformin in the treatment of DM and epilepsy.
Results
Our analyses of the clinical data suggest a significant association between pathogeneses of epilepsy and DM. Further, both agmatine and metformin appear to be multimodal therapeutic agents and have robust antiepileptogenic and antidiabetic properties. Data from animal and clinical studies largely support the use of metformin/agmatine as a double-edged pharmacotherapeutic agent against DM and epilepsy, particularly in their concurrent pathological occurrences.
Conclusion
The present review explores the evidences and available data on possible uses of metformin/agmatine as pertinent antidiabetic and antiepileptic agents. Our hope is that this will stimulate further research on the therapeutic actions of these multimodal agents, particularly for subject-specific clinical outcomes.
... Dementia is strongly intertwined with degenerative and functional diseases of the central nervous system, resulting in various neurochemical, neurophysiological, and anatomical abnormalities. 59 Dementia patients were found to have lower test scores for memory, cognitive flexibility, fast data processing, and psychomotor efficacy. 60 The link between poor insulin and the CNS greatly increases the risk of memory loss. ...
... 60 The link between poor insulin and the CNS greatly increases the risk of memory loss. 59 Impaired glucose and energy metabolism 61 hyperglycemia, 62 reduced insulin sensitivity, 44 insulin resistance and insulin/insulin receptor dysfunction, 63 changes in hippocampal synaptic plasticity and transmission, 64 increased advanced glycation end products (AGE) that cause memory dysfunction in dementia-like conditions, 65 Poor insulin caused memory loss in rats, which was linked to increased cholinergic activity and oxidative stress, leading to dementia. 66 Insulin resistance causes cognitive impairment in type 2 diabetes. ...
Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.
... For instance, it was reported that I 2 imidazoline drugs inhibit amyloid-β (Aβ)-induced neuronal toxicity by reducing Erk1/2 activation (Montolio, Gregori-Puigjané, Pineda, Mestres, & Navarro, 2012). In addition, chronic treatment with agmatine, an endogenous imidazoline receptor ligand, significantly alleviated cognitive deficits induced in diabetic rats (Bhutada et al., 2012). The exact mechanisms by which I 2 ligands may exert their neuroprotective effects are not fully understood and require further investigation. ...
... However, despite these beneficial effects, the role of selective I 2 receptor ligands on neurodegeneration and amyloid pathology has not been explored. Interestingly, results from two studies demonstrated that treatment with the putative endogenous imidazoline receptor ligand agmatine led to improvements of cognitive dysfunction in rat models of diabetes (Bhutada et al., 2012;Kang et al., 2017), although this drug has higher affinity for the I 1 receptor sub type. Most recently, a study has shown that administration of idazoxan, a mixed α 2 -adrenoceptor antagonist and I 2 receptor ligand, in the APP/PS1 and in APP-knock-in models of AD, resulted in reduced Aβ load and mitigated the cognitive impairments. ...
Background and Purpose
Activation of type 2 imidazoline receptors has been shown to exhibit neuroprotective properties including anti‐apoptotic and anti‐inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the imidazoline‐2 ligand BU224 in a model of amyloidosis.
Experimental Approach
Six‐month‐old female transgenic 5XFAD and wild‐type (WT) mice were treated intraperitoneally with 5‐mg·kg⁻¹ BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, elisa and qPCR. Effects of BU224 on amyloid precursor protein (APP) processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells.
Key Results
BU224 treatment attenuated spatial and perirhinal cortex‐dependent recognition memory deficits in 5XFAD mice. Fear‐conditioning testing revealed that BU224 also improved both associative learning and hippocampal‐ and amygdala‐dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro‐inflammatory cytokines IL‐1β and TNF‐α and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a threefold reduction in amyloid‐β (Aβ)‐induced functional changes in NMDA receptors.
Conclusion and Implications
Sub‐chronic treatment with BU224 restores memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.
... Agmatine is also a potent antioxidant and anti-inflammatory agent [45,47,48]. It has been found that several diseases benefit from exogenous agmatine administration [45,[49][50][51]. There are several reports on the effects of agmatine on oxidative stress-mediated complications in various experimental models [52][53][54][55]. ...
... Agmatine also provides potent hepatoprotection, probably via scavenging free radicals and boosting liver antioxidant enzymes [57]. It has been found that agmatine increased glutathione level, enhanced the activity of antioxidant enzymes such as SOD, and prevented cellular proteins and lipids damage [50,55,57,87,88]. One of the most important signaling pathways for the effects of agmatine on cellular enzymatic antioxidants could be mediated through the nuclear receptor nuclear factor erythroid 2-related factor 2 (Nrf2) [89,90]. ...
... Thick arrows and thick lines indicate induction and inhibition of the corresponding biological pathways, respectively. ODC ornithine decarboxylase (Satriano et al. 1998;Demady et al. 2001;Regunathan and Piletz 2003;Satriano 2004) Zomkowski et al. (2002), Aricioglu and Altunbas (2003), Zeidan et al. (2007), Kotagale et al. (2013), Moretti et al. (2015), Kudlow et al. (2016), Gawali et al. (2017), Chen et al. (2018) Clinical studies Remission of major depression independently of serotonergic mechanisms Shopsin (2013) Anxiety Preclinical study Anxiolytic activity via modulation of NO signaling pathway Aricioglu and Altunbas (2003), Lavinsky et al. (2003), Gong et al. (2006), Gawali et al. (2017) Clinical study Not reported yet Neuropathic pain Preclinical study Analgesic effect by inhibiting NOS activity and blocking NMDA receptors Enhancement of antinociceptive effect of morphine by activating α 2adrenogeric receptor Kolesnikov et al. (1996), Horváth et al. (1999, Fairbanks et al. (2000), Yeşilyurt and Uzbay (2001), Courteix et al. (2007) Clinical study Pain relief in patients suffering from lumbar disc-associated radiculopathy Keynan et al. (2010) Cognitive decline Preclinical study Promotion of memory consolidation Improvement of age-related cognitive decline by lowering oxidative stresses Increased agmatine in hippocampus in rats trained on learning task Improvement of cognitive deficit by reducing Aβ and phosphorylated tau in Alzheimer's disease model animals Arteni et al. (2002), Liu et al.(2008a, b), Bergin and Liu (2010), Leitch et al. (2011), Bhutada et al. (2012), Rushaidhi et al. (2012aRushaidhi et al. ( , 2013a, Kang et al. (2017) Clinical study Not reported yet, except for the decreased agmatine and altered agmatine metabolism in the brain of aged-individuals and patients with Alzheimer's disease Rushaidhi et al. (2012b), Liu et al. (2014), Cinco et al. (2015) Dependence on drugs Preclinical study Prevention of ethanol conditioning and withdrawal by acting on imidazoline receptors Alleviation of nicotine withdrawal with protecting liver from oxidative damage Prevention of morphine dependence and withdrawal Reduction of methamphetamine dependency Kolesnikov et al. (1996), Aricioglu-Kartal and Uzbay (1997), Uzbay et al. (2000), Aricioglu-Kartal and Regunathan (2002), Su et al. (2008) Antihyperglycemic effect by promoting glucose uptake by muscle and preventing gluconeogenesis in liver through enhanced β-endorphin secretion Repression of weight gain caused by high-fat diet and improvement of insulin sensitivity by activating cAMP-dependent PKA signaling Sener et al. (1989), Shepherd et al. (1996), Nissim et al. (2006Nissim et al. ( , 2014, Su et al. (2009), Chang et al. (2010 Clinical study Not reported yet fungus Aspergillus oryzae, which is widely used for the production of various Asian fermented foods. Zomkowski et al. (2002) first reported the antidepressantlike effect of agmatine. ...
... The effects of agmatine on learning and memory enhancement were also confirmed in aged rats, and exogenous agmatine suppressed age-related elevation of NOS activity in the hippocampus and prefrontal cortex (Rushaidhi et al. 2012a(Rushaidhi et al. , 2013b, suggesting that these facilitatory effects of agmatine were exerted by lowering oxidative stress through NOS inhibition. In fact, chronic agmatine administration substantially attenuated oxidative stresses, such as elevated lipid peroxidation and reduced glutathione levels, in the hippocampus of diabetic rats, accompanied by improved cognitive performance and hyperglycemia (Bhutada et al. 2012). Mass spectrometric and microscopy analyses revealed increased hippocampal agmatine in rats trained in water maze tasks (Liu et al. 2008a;Leitch et al. 2011;Rushaidhi et al. 2013a). ...
Agmatine, a natural polyamine produced from arginine by arginine decarboxylase, was first discovered in 1910, but its physiological significance was disregarded for a century. The recent rediscovery of agmatine as an endogenous ligand for α2-adrenergic and imidazoline receptors in the mammalian brain suggests that this amine may be a promising therapeutic agent for treating a broad spectrum of central nervous system-associated diseases. In the past two decades, numerous preclinical and several clinical studies have demonstrated its pleiotropic modulatory functions on various molecular targets related to neurotransmission, nitric oxide synthesis, glucose metabolism, polyamine metabolism, and carnitine biosynthesis, indicating potential for therapeutic applications and use as a nutraceutical to improve quality of life. An enzymatic activity of arginine decarboxylase which produces agmatine from arginine was low in mammals, suggesting that a large portion of the agmatine is supplemented from diets and gut microbiota. In the present review, we focus on and concisely summarize the beneficial effects of agmatine for treating depression, anxiety, neuropathic pain, cognitive decline and learning impairment, dependence on drugs, and metabolic diseases (diabetes and obesity), since these fields have been intensively investigated. We also briefly discuss agmatine content in foodstuffs, and a simple approach for enhancing agmatine production using the filamentous fungus Aspergillus oryzae, widely used for the production of various Asian fermented foods.
... They also demonstrated significantly increased levels of agmatine in entorhinal and perirhinal cortices in aged rats as compared with middle-aged and younger ones and in postrhinal and temporal cortices in aged and middle-aged rats compared with young rats. A dramatic decrease in the levels of agmatine has been detected in prefrontal cortex of aged rats relative to middle-aged and younger ones 43,46 . ...
... This hypothesis is consistent with a previous study reporting that agmatine administration significantly improved memory in aged rats and suppressed age-related elevation in total NOS activity. Thus, agmatine may have ameliorated the cognitive impairment induced by aging via regulating total NOS expression 46 . ...
Objective: Agmatine, the decarboxylation product of arginine produced by arginine decarboxylase, is a novel neurotransmitter and exists in the mammalian brain. Agmatine has been reported to modulate cognitive functions, including learning and memory. Methods: In the present study, we evaluated the effects of agmatine on cognitive performance and oxidative damage in intracerebroventricular (i.c.v.) streptozotocin (STZ) model of Alzheimer’s disease (AD). Adult male Sprague-Dawley rats were injected STZ (3mg/kg, i.c.v, bilaterally) on days 1 and 3. The learning and memory patterns were assessed by using passive avoidance, Morris water maze, and closed field activity tests. Also, malondialdehyde (MDA), glutathione (GSH) levels and myeloperoxidase (MPO) activity have been determined as the parameters of oxidative damage. The behavioral tests were performed after 14 days from the first injection of STZ. Rats with impaired learning and memory performance were treated with intraperitoneal (i.p.) agmatine (40 mg/kg) twice daily for 7 days. After agmatine treatment, rats were subjected to the aforementioned behavioral tests again. Immediately after decapitation of the rats, the brains were collected and analyzed for oxidative damage parameters. Results: Agmatine improved the STZ-induced both spatial and emotinal memory impairment and oxidative damage. Findings of the study demonstrated the effectiveness of agmatine in reversing the cognitive deficits as well as the oxidative damage caused by i.c.v STZ. Conclusion: Taken together, our results have provided experimental evidence suggesting a possible therapeutic potential of agmatine as a regulator in etiopathogenesis of neurodegenerative diseases such as Alzheimer’s disease. © 2016, Cukurova Univ Tip Fakultesi Psikiyatri Anabilim Dali. All rights reserved.
... The ameliorative actions of agmatine against the pathological AD-diabetes axis have also been proposed in several recent studies. For example, agmatine elicited significant memory-and cholinergic signalling-enhancing and antioxidant actions in a STZ-induced rodent model of diabetes (Bhutada et al., 2012). Aricioglu's group observed robust repression of STZ-induced oxidative damage and behavioural alterations mediated by intraperitoneal application of exogenous agmatine (Sirvanci-Yalabik et al., 2016). ...
Agmatine, an endogenous polyamine derived from L-arginine, elicits tremendous multimodal neuromodulant properties. Alterations in agmatinergic signalling are closely linked to the pathogeneses of several brain disorders. Importantly, exogenous agmatine has been shown to act as a potent neuroprotectant in varied pathologies, including brain ageing and associated comorbidities. The antioxidant, anxiolytic, analgesic, antidepressant and memory-enhancing activities of agmatine may derive from its ability to regulate several cellular pathways; including cell metabolism, survival and differentiation, nitric oxide signalling, protein translation, oxidative homeostasis and neurotransmitter signalling. This review briefly discusses mammalian metabolism of agmatine and then proceeds to summarize our current understanding of the neuromodulation and neuroprotection mediated by agmatine. Further, the emerging exciting bidirectional links between agmatine and the resident gut microbiome and their implications for brain pathophysiology and ageing are also discussed.
... Furthermore, agmatine also prevented scopolamine-induced memory impairment [111]. The similar effect was observed in streptozotocin-induced memory deficits in diabetic rats [112] and in morphine or lipopolysaccharide-induced memory impairment in mice [113]. Agmatine also showed memory-enhancing effect in AD-like neurodegenerative diseases. ...
Cognitive disorders such as dementia, amnesia, and delirium primarily affect attention, learning, reasoning, planning, judgment, memory, and other thought processes. Irreversible dementias associated with Alzheimer’s disease and Lewy bodies have become the detrimental clinical problems. Since currently available drugs have very limited therapeutic value, there is an emerging need to find out novel targets for the development of future drugs by elucidating the underlying complex pathophysiological mechanisms and identifying the key mediators. The discrete brain regions have been involved in the acquisition and specific type information storage. Moreover, various neuropeptides integrate and process cognition-related signals in the brain by forming neuronal networks with each other and classical neurotransmitters systems. Improvement of functional impairments and inhibition of progressive neurodegeneration by some neuropeptides and neurotransmitters have paved the way to develop nonpeptidergic therapeutic agents with good brain penetration. This chapter summarizes process of memory formation, key neuroanatomical regions, and mediators involved in the cognitive processes and disorders.
... Administration of agmatine to animals may exert antidepressant and anxiolytic activity, cognitive enhancement and neuroprotective effects in animal models. It is hypothesized that agmatine attenuates inflammation (Neis et al., 2014;Sahin et al., 2016;Turan et al., 2017) through antioxidative NOS inhibitory actions (Bhutada et al., 2012;Chai et al., 2016;Freitas et al., 2015) or NMDA receptor antagonistic activity (Singh et al., 2017). It also exerts antiapoptotic effects Condello et al., 2011) and BDNF signaling promoting effects (Gawali et al., 2016;Olescowicz et al., 2018). ...
L-Arginine pathway metabolites appear to play differential roles in the pathogenesis of major depressive disorder (MDD). Studies have revealed an antidepressant and anxiolytic effect of agmatine and putrescine. Possible mechanisms of these effects include inhibition of nitric oxide synthase and N-methyl-D-aspartate receptors. The present study sought to determine whether MDD is associated with altered levels of arginine metabolites and whether these metabolites are associated with depression, anxiety and stress severity. Seventy seven MDD patients 21-65 years of age with a minimum score of 18 on the Hamilton Depression Scale, and 27 age and sex matched healthy controls (HC) were included. Patients with uncontrolled physical diseases, abnormal routine lab tests, other psychiatric diagnoses, or under psychotropic medication were excluded. HC subjects were recruited from the community. Rating instruments included Hamilton Depression and Anxiety Scales, Beck Depression and Anxiety Inventory and Perceived Stress Scale. Fasting blood was drawn between 8:30 and 11:00 a.m. and High Performance Liquid Chromatography (HPLC) was used to measure plasma arginine metabolites. ADMA (Asymmetrical dimethylarginine) and putrescine were significantly lower while SDMA (Symmetric dimethylarginine), agmatine and ornithine were significantly higher in MDD patients (p˂0.05). Depression, anxiety and stress severity were negatively correlated with ADMA and putrescine (p˂0.05). Stress was positively correlated with citrulline, NOHA (N-omega-hydroxy-nor-l-arginine), SDMA, agmatine and ornithine (p˂0.05). Lower putrescine levels predicted depression diagnosis (p = 0.039) and depression severity (p = 0.003). Low ADMA level predicted depression severity as well. Arginine pathway metabolites are associated with the pathophysiology of depression. Putrescine may be a biomarker to predict MDD.
... Therefore, there is a high possibility that similar effects observed in ICH. The neurological conditions, which may further benefit from this class of agents, include dementia and memory impairment [91,92], autoimmune encephalomyelitis [93], Huntington's disease [94], tolerance and dependence to opioid analgesics [95,96], pain conditions [97,98], and depression [23] (see Table 2). However, the described neuroprotective effects should be interpreted with caution. ...
Intracerebral hemorrhage (ICH), which accounts for 10-15% of all strokes, leads to higher morbidity and mortality compared with other stroke subtypes. Hypertension has been recognized as a major risk factor for ICH. Current antihypertensive options have not been fully effective for either prevention of ICH or ameliorating its complications. Therefore, attempts should be made to use novel antihypertensive medications for more effective management of blood pressure (BP) in the acute phase of ICH. Imidazoline receptors (IR) agonists can potentially be effective agents for BP control with the adjunctive ability to attenuate post-ICH brain injury. IR agonists render neuroprotective effects including inhibition of inflammatory reactions, apoptotic cell death, excitotoxicity, and brain edema. Given these properties, the present review aims to focus on the application of IR agonists for managing BP in ICH patients.
... Bhutada et al. reported that agmatine ameliorates oxidative stress due to lipid peroxidation in the rat brain. 49 The suppression of lipid peroxidation by agmatine in the present study may have been mediated by the detoxification of peroxy radicals and ROS, which further supports the antioxidant role of agmatine. ...
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer’s disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and nonmotor symptoms. The neuropathological hallmarks of PD are well reported, but the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, and neuroinflammation play vital roles in the progress of the disease. The current study was established to investigate the neuroprotective effect of agmatine on a rotenone (ROT)-induced experimental model of PD. Adult male Sprague Dawley rats were subcutaneously injected with ROT at a dose of 2 mg/kg body weight for 35 days. Agmatine was injected intraperitoneally at 50 and 100 mg/kg body weight, 1 h prior to ROT administration. ROT-treated rats that received agmatine showed better performance on beam walking and an elevated number of rears within the cylinder test. In addition, agmatine reduced midbrain malondialdehyde as an indication of lipid peroxidation, pro-inflammatory cytokines including tumor necrosis factor alpha and interleukin-1β, and glial fibrillary acidic protein. Moreover, agmatine was responsible for preventing loss of tyrosine hydroxylase-positive neurons. In conclusion, our study showed that agmatine possesses a dose-dependent neuroprotective effect through its antioxidant and anti-inflammatory activities. These findings need further clinical investigations of agmatine as a promising neuroprotective agent for the future treatment of PD.
... 3. NIC+AG group: rats were treated by AG (10 mg/kg/day) orally [22] and NIC10 mg/kg/day by IP injection for 9 weeks. ...
Abstract
Introduction: Nicotine (NIC), the chief alkaloid in tobacco, believed to be an active agent responsible for lungassociated
diseases. This protocol targeted to analyze the ameliorating effect of agmatine (AG) on NIC induced
lung damage.
Mateiral and methods: Forty-five adult male rats were divided into: Control group received intraperitoneal (IP)
injection of distilled water, 2) NIC group recieved NIC (10 mg/kg/day) IP and 3) (NIC+AG) group treated by AG (10
mg/kg/day) orally+NIC (10 mg/kg/day) by IP injection for 9 weeks. Total serum protein, triglycerides (TGs), total
cholesterol (TC), high density lipoprotein (HDL), Low density lipoprotein cholesterol (LDL-C), malondialdehyde
(MDA), superoxide dismutase (SOD), reduced glutathione (GSH) and vascular cell adhesion molecule 1 (VCAM-
1) were estimated. Lung specimens were prepared and stained with H&E, Masson trichrome and immunehistochemical
stains for assessment of transforming growth factor beta 1 (TGF-β1) and Bax. Morphometric study
followed by statistical analysis were done.
Results: NIC group showed elevation in serum levels of total protein, TC, LDL-C, TGs, MDA and VCAM-1 with
evident diminishing in the serum levels of HDL-C, SOD, and GSH. Apoptosis and damage of alveolar epithelium
and bronchiolar cells, marked fibrosis, inflammatory cell infiltrate and congestion of blood vessels were observed.
Marked increase in the mean alveolar wall thickness, mean area% of collagen fibers deposition, mean area% of
TGFβ1 immuno-expression and mean number of Bax immune positive cells while a decrease in the mean linear
intercept were detected. AG co-administered with nicotine ameliorated these biochemical, histopathological and
morphometric changes.
Conclusion: AG ameliorates NIC induced lung damage in rats through improving the biochemical parameters
and by decreasing TGF-ß1 and Bax immunoexpression.
... Regarding the ability of agmatine to improve cognitive performance in rodents, it was shown to facilitate spatial working memory in the Morris water maze test (Liu and Bergin, 2009), and memory in the inhibitory avoidance task in adult rats (Arteni et al., 2002). Agmatine was also able to prevent LPS-induced neuroinflammation and memory deterioration (Zarifkar et al., 2010), and streptozotocin-induced memory impairments associated with oxidative stress (increased lipid peroxidation, decreased reduced glutathione) and reduction on choline esterase activity (Bhutada et al., 2012). In addition, agmatine inhibited morphine-induced memory impairment in the step-down inhibitory avoidance test in mice (Lu et al., 2010) and prevented hippocampal ERK and Akt inactivation induced by scopolamine, suggesting that this endogenous/s substance may be a candidate against amnesia (Moosavi et al., 2012). ...
Agmatine is a neuromodulator that regulates multiple neurotransmitters and signaling pathways. Several studies have focused on elucidating the mechanisms underlying the neuroprotective effects of this molecule, which seems to be mediated by a reduction in oxidative damage, neuroinflammation, and proapoptotic signaling. Since these events are implicated in acute and chronic excitotoxicity-related disorders (ischemia, epilepsy, traumatic brain injury, spinal cord injury, neurodegenerative, and psychiatric disorders) as well as in nociception, agmatine has been proposed as a therapeutic strategy for the treatment of central nervous system (CNS) disorders. Agmatine also stimulates the expression of trophic factors and adult neurogenesis, contributing to its ability to induce endogenous repair mechanisms. Therefore, considering its wide range of biological effects, this review summarizes the current knowledge about its protective and regenerative properties in the CNS.
... The core finding of the present study is that, administration of relevant doses of agmatine is remarkably neuroprotective in rats against 6-Hydroxydopamine-induced neurotoxicity. We have chosen the dose of agmatine (2.5, 5 and 10 mg/kg., i.p.) according to the previous studies done in our laboratory 3 . There are no previous reports on the protective effect of agmatine in 6-Hydroxydopamine induced neurotoxicity, an animal model for Parkinson's disease. ...
... The ability of agmatine to afford neuroprotection has been described firstly by Gilad et al. (1996), followed by a variety of subsequent studies in several experimental models in animals, namely brain ischemia or hypoxia (Ahn et al., 2011(Ahn et al., , 2015Cui et al., 2012;Feng et al., 2002;Huang et al., 2013;Kim et al., 2004Kim et al., , 2006Kim et al., , 2010Kim et al., , 2015Kuo et al., 2011;Lee et al., 2009;Mun et spinal cord injury Gilad and Gilad, 2000;Kim et al., 2011;Kotil et al., 2006;Park et al., 2013;Yu et al., 2003;Yu et al., 2000), 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-mediated toxicity (Gilad et al., 2005;Matheus et al., 2012), glutamate and/or NMDAinduced neurotoxicity (Olmos et al., 1999;Wang et al., 2006;Zhu et al., 2003), glucocorticoid (Freitas et al., 2016;Zhu et al., 2006) and rotenone-mediated neurotoxicity (Condello et al., 2011(Condello et al., , 2012. Agmatine also provides beneficial effects against deleterious brain effects induced by betaamyloid (Bergin and Liu, 2010), streptozotocin (Bhutada et al., 2012;Moosavi et al., 2014;Song et al., 2014), scopolamine (Moosavi et al., 2012;Utkan et al., 2012), morphine (Lu et al., 2010), bacterial lipopolysaccharide (LPS) (Zarifkar et al., 2010), and improves memory in aged rats (Rushaidhi et al., 2012(Rushaidhi et al., , 2013. Anticonvulsive (Feng et al., 2005;Su et al., 2004;Xu et al., 2014) and antinociceptive (Bhalla et al., 2013;Courteix et al., 2007;Gadotti et al., 2006;Hou et al., 2003;Kekesi et al., 2004;Onal and Soykan, 2001;Paszcuk et al., 2007;Roerig, 2003;Santos et al., 2005) effects were also observed following the administration of agmatine. ...
Major depressive disorder is the most common psychiatric disorder with lifetime prevalence of up to 20% worldwide. It is responsible for more years lost to disability than any other disorder. Despite the fact that current available antidepressant drugs are safe and effective, they are far from ideal. In addition to the need to administer the drugs for weeks or months to obtain clinical benefit, side effects are still a serious problem. Agmatine is an endogenous polyamine synthesized by the enzyme arginine decarboxylase. It modulates several receptors and is considered as a neuromodulator in the brain. In this review, studies demonstrating the antidepressant effects of agmatine are presented and discussed, as well as, the mechanisms of action related to these effects. Also, the potential beneficial effects of agmatine for the treatment of other neurological disorders are presented. In particular, we provide evidence to encourage future clinical studies investigating agmatine as a novel antidepressant drug.
... Four groups were utilized in the current research (each composed of eight rats): normal group, rats were receiving distilled water (nicotine vehicle) by ip injection; nicotine group, rats were given nicotine (10 mg/kg/day, ip; Morley and Garner 1990) for 9 weeks; AGM group, rats were administered AGM (10 mg/kg/day, orally; Bhutada et al. 2012) and receiving nicotine vehicle for 9 weeks; and AGM-nicotine group, rats were given AGM with nicotine for 9 weeks. AGM treatment was started 1 week prior to the administration of nicotine and continued to the end of the experiment. ...
Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.
... Agmatine, (4-aminobutyl)guanidine-AGM, is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine [19,20]. AGM is a putative neurotransmitter and an intermediate in polyamine biosynthesis [21]. ...
The aim of the study is to investigate the hypothesis that agmatine (AGM) enhances blood brain barrier (BBB) compounds properties in experimental autoimmune encephalomyelitis (EAE), which is an established animal model for studying multiple sclerosis (MS). Wild-type (WT) and knockout (KO) CBA/H iNOS-/- mice, 3 months old (15 ± 5 g) were used for EAE induction by myelin basic protein (MBP) dissolved in complete Freund's adjuvant (CFA). The animals were divided into control, CFA, EAE, EAE + AGM and AGM groups. After the development of full clinical remission, the animals were sacrificed and the immunohistochemical and biochemical examinations were performed in brain homogenates. We had noticed the increased expressions of occludin in WT and KO mice with EAE + AGM, compared to EAE groups in which these expressions were significantly decreased compared to the controls. The significant elevations of matrix metalloproteinases (MMPs)-MMP-3 and MMP-9 in WT and KO EAE animals were decreased during AGM treatment in both groups. AGM application post EAE in WT and KO mice caused decreased level of Iba-1 stain, compared to EAE groups. The obtained results suggest beneficial AGM effects in EAE on BBB components, which might be useful for novel therapeutic strategies in MS.
... The increase in hepatic GSH concentration after CPZ+AGM administration results from the inhibition of GSH efflux across the canalicular membrane of hepatocyte, since GSH represents the major osmotic solute for the generation of bile salt-independent bile flow. The protective effect of AGM observed in this respect can be attributed to its high efficacy in scavenging various types of free radicals, and enhancement of antioxidant enzymes activities (Bhutada et al. 2012). ...
The present study focused on potentially beneficial effects of agmatine on oxidative stress development in the liver during chlorpromazine treatment in rats. We wanted to examine the role of reactive oxygen species and efficiency of antioxidant protection through the determination of malondylaldehyde and total glutathione concentrations in rat liver homogenate, as well as plasma concentrations of malonylaldehyde and sulfhydryl groups after the treatment. Also, liver tissue sections were examined to follow histological changes. Chlorpromazine was applied intraperitoneally at a single dose of 38.7 mg/kg b.w. The second group was treated with both chlorpromazine (at a single dose of 38.7 mg/kg b.w.) and agmatine (at a single dose of 75 mg/kg b.w.). Agmatine was applied immediately after the chlorpromazine. The control group was treated with 0.9% saline solution in the same manner. Rats were sacrificed by decapitation 24 h after the treatment and biochemical and immunohistochemical examinations were performed. Analysis of data showed that treatment with agmatine significantly attenuated the oxidative stress indicators as evidenced by lowering malonylaldehyde concentrations in the liver and in plasma while not affecting liver concentrations of total glutathione and plasma concentration of sulfhydryl groups. Additionally, histological evaluation revealed the improvement of liver damage in this respect. The presented data indicated that intraperitoneally administered agmatine protects against chlorpromazine-induced liver disease in rats.
... Our findings showed that diabetic rats did not exhibit damage to the short-term 60 min retention interval, in agreement with the observations made by Ceretta et al. (2012), which used a 90 min retention interval. However, it is important to note that some other studies revealed a significant effect of diabetes induction using the NOR task, applying a shorter interval between trial 1 and trial 2 and/or a longer object exploration time in each trial (Bhutada et al. 2012;King et al., 2013). Hence, studies should be conducted to clarify which NOR task protocol is the most sensitive regarding short-term memory in diabetic animals. ...
Type 1 diabetes mellitus (T1DM) progressively affects cognitive domains, increases blood-brain barrier (BBB) permeability and promotes neurovascular impairment in specific brain areas. Physical exercise, on the other hand, has beneficial effects on brain functions, improving learning and memory. This study investigated the effects of treadmill training on cognitive and motor behavior, and on the expression of proteins related to BBB integrity, such as claudin-5 and aquaporin-4 (AQP4) in the hippocampus and striatum in diabetic rats. For this study, 60 Wistar rats were divided into four groups (n=15 per group): non-trained control (NTC), trained control (TC), non-trained diabetic (NTD), trained diabetic (TD). 30 days after diabetic induction by streptozotocin injection, the exercise groups were submitted to 5 weeks of running training. After that, all groups were assessed in a novel object- recognition task (NOR) and the rotarod test. Additionally, claudin-5 and AQP4 levels were measured using biochemical assays. The results showed that exercise enhanced NOR task performance and rotarod ability in the TC and TD animals. Diabetes produced a decrease in claudin-5 expression in the hippocampus and striatum and reduced AQP4 in the hippocampus. Exercise preserved the claudin-5 content in the striatum of TD rats, but not in the hippocampus. The reduction of AQP4 levels produced by diabetes was not reversed by exercise. We conclude that exercise improves short-term memory retention, enhances motor performance in diabetic rats and affects important structural components of the striatal BBB. The results obtained could enhance the knowledge regarding the neurochemical benefits of exercise in diabetes.
Copyright © 2015. Published by Elsevier B.V.
... The memory enhancing effects of agmatine were also confirmed in streptozotocin-induced diabetic rats, which display learning and memory deficits associated with increased lipid peroxidation, reduced glutathione, and elevated choline esterase activity. Chronic treatment with agmatine (30 days) rescued cognitive performance, decrease hyperglycemia, oxidative stress, and choline esterase activity in diabetic rats (78). ...
Agmatine, a cationic polyamine synthesized after decarboxylation of L-arginine by the enzyme arginine decarboxylase, is an endogenous neuromodulator that emerges as a potential agent to manage diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, there is increasing number of preclinical studies demonstrating the beneficial effects of exogenous agmatine administration on depression, anxiety, hypoxic ischemia, nociception, morphine tolerance, memory, Parkinson`s disease, Alzheimer`s disease, traumatic brain injury related alterations/disorders and epilepsy. The aim of this review is to summarize the knowledge about the effects of agmatine in CNS and point out its potential as new pharmacological treatment for diverse neurological and neurodegenerative diseases. Moreover, some molecular mechanisms underlying the neuroprotective effects of agmatine will be discussed.
... Note, however, that Ab aggregate formation is also associated with traumatic brain injuries; therefore, this paradigm is not a unique model of Alzheimer's dementia. Another study showing that agmatine treatment can reduce memory impairments in a diabetic rat model [126], might also be relevant because malfunctions in glucose metabolism have been implicated in Alzheimer's dementia. Thus, the evidence hints that agmatine has cognitive enhancement properties and might be a novel nootropic with therapeutic potential in Alzheimer's dementia. ...
Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence of XXX, and highlights challenges and opportunities for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.
... The current results are in accord with previous findings indicating the cognitive-enhancing properties of agmatine in diverse animal models of brain injury. For instance, the repeated administration of agmatine (5–40 mg/kg, i.p.) prevented learning and memory impairments in rodents induced by infusion of aggregated beta-amyloid(25-35) peptide [7] , lipopolysaccha- ride [71], streptozotocin [9] and scopolamine [49]. Moreover, recent studies [44,45,67] have demonstrated that spatial learning in rodents induces elevation in agmatine levels at synapses in the rat hippocampus, providing further evidence of its participation in learning and memory processes. ...
We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in olfactory, cognitive, emotional and motor functions associated with time-dependent disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in several models of neuronal cellular damage. In the present study we demonstrated that repeated treatment with agmatine (30mg/kg, i.p.) during 5 consecutive days increased the survival rate (from 40% to 80%) of 15-month-old C57BL/6 female mice infused with a single intranasal (i.n.) administration of MPTP (1mg/nostril), improving the general neurological status of the surviving animals. Moreover, pretreatment with agmatine was found to attenuate short-term social memory and locomotor activity impairments observed at different periods after i.n. MPTP administration. These behavioral benefits of exogenous agmatine administration were accompanied by a protection against the MPTP-induced decrease of hippocampal glutamate uptake and loss of dopaminergic neurons in the substantia nigra pars compacta of aging mice, without altering brain monoamine oxidase B (MAO-B) activity. These results provide new insights in experimental models of PD, indicating that agmatine represents a potential therapeutic tool for the management of cognitive and motor symptoms of PD, together with its neuroprotective effects.
... Note, however, that Ab aggregate formation is also associated with traumatic brain injuries; therefore, this paradigm is not a unique model of Alzhei- mer's dementia. Another study showing that agmatine treatment can reduce memory impairments in a diabetic rat model [126], might also be relevant because malfunctions in glucose metabo- lism have been implicated in Alzheimer's dementia. Thus, the evidence hints that agmatine has cognitive enhancement properties and might be a novel nootropic with therapeutic potential in Alzheimer's dementia. ...
Plasma agmatine concentrations are elevated significantly in depressed patients compared to healthy controls. Treatment with the antidepressant bupropion normalized plasma agmatine levels. Correlational evidence is presented that a change in plasma agmatine levels may lead to similar changes in platelet I1 imidazoline receptors.
Agmatine, a naturally occurring polyamine derived from arginine via arginine decarboxylase, has been shown to play multifaceted roles in the mammalian body, impacting a wide range of physiological and pathological processes. This comprehensive review delineates the significant insights into agmatine's pharmacological profile, emphasizing its structure and metabolism, neurotransmission and regulation, and pharmacokinetics and function. Agmatine's biosynthesis is highly conserved across species, highlighting its fundamental role in cellular functions. In the brain, comparable to established neurotransmitters, agmatine acts as a neuromodulator, influencing the regulation, metabolism, and reabsorption of neurotransmitters that are key to mood disorders, learning, cognition, and the management of anxiety and depression. Beyond its neuromodulatory functions, agmatine exhibits protective effects across various cellular and systemic contexts, including neuroprotection, nephroprotection, cardioprotection, and cytoprotection, suggesting a broad therapeutic potential.
The review explores agmatine's interaction with multiple receptor systems, including NMDA, α2-adrenoceptors, and imidazoline receptors, elucidating its role in enhancing cell viability, neuronal protection, and synaptic plasticity. Such interactions underpin agmatine's potential in treating neurological diseases and mood disorders, among other conditions. Furthermore, agmatine's pharmacokinetics, including its absorption, distribution, metabolism, and excretion, are discussed, underlining the complexity of its action and the potential for therapeutic application. The safety and efficacy of agmatine supplementation, demonstrated through various animal and human studies, affirm its potential as a beneficial therapeutic agent.
Conclusively, the diverse physiological and therapeutic effects of agmatine, spanning neurotransmission, protection against cellular damage, and modulation of various receptor pathways, position it as a promising candidate for further research and clinical application. This review underscores the imperative for continued exploration into agmatine's mechanisms of action and its potential in pharmacology and medicine, promising advances in the treatment of numerous conditions.
Agmatine, Polyamine, Cytoprotection, Neurotransmitter, Metabolism
Background and Purpose
A high‐fat diet (HFD) is a common risk factor for Type 2 diabetes mellitus (T2DM) and its associated cognitive impairments. In models of diabetes, resveratrol, a modulator of SIRT1, regulates the fasting glucose and antioxidant levels, as well as the lipid profile. Resveratrol may also alleviate the cognitive dysfunctions associated with diabetes.
Experimental Approach
Albino rats were fed a HFD, (60% kcal fat) after treatment with streptozotocin (45 mg·kg⁻¹,i.p., single dose) to induce an experimental model of T2DM. After 14 weeks of the animals in confirmed diabetic condition, they were treated with metformin (200 mg·kg⁻¹,i.p.) or resveratrol (50 or 100 mg·kg⁻¹,i.p.) for 4 weeks. Levels of oxidative‐nitroso‐stress, SIRT1, TGF‐β1, inflammation and cholinergic activity were determined in plasma, hippocampus and cerebral cortex. A battery of behavioural studies associated with learning memory were performed during and after the experimental protocol.
Key Results
Treatment with resveratrol attenuated the increased glucose levels (pre‐ and post‐prandial), impaired glucose tolerance, HbA1c, and decreased the body weights of the T2DM rats. Moreover, resveratrol ameliorated the impaired learning and memory associated with increased SIRT1 and decreased TGF‐β1, TNF‐α, oxidative‐nitroso‐stress, and cholinergic activities in the plasma and the brains of the T2DM animals.
Conclusion and Implication
Our results demonstrated that SIRT1 modulation interacted with TGF‐β1 signalling, and mitigated hyperglycaemia and subsequent learning‐memory impairments in the T2DM animals. Our study also suggested novel therapeutic targets, including TGF‐β1, which may add to our knowledge of resveratrol, when used to treat impaired memory associated with diabetes.
Objectives:
Diabetes mellitus associated cognitive impairment is suggested to be due to oxidative stress. Considering the anti-diabetic, antioxidant, antihyperlipidemic, and anti-inflammatory effects of Zingiber officinale, the present study aimed to investigate its effect on memory and oxidative stress factors in streptozotocin (STZ)-induced diabetic rats.
Methods:
The rats were allocated into five groups: Control, Diabetic, Diabetic + Ginger 100, Diabetic + Ginger 200, and Diabetic + Ginger 400. Following diabetes induction by STZ (60 mg/kg), 100, 200, or 400 mg/kg Ginger was given for eight weeks. Passive avoidance test (PA) was done and thiol, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) measurements were carried out in the brain.
Results:
The latency into the dark compartment decreased (p<0.001) and the number of entries and time spent in the dark chamber increased in the Diabetic group compared to the Control (p<0.001 for all). All three doses of extract improved performance of the rats in the PA test (p<0.001 for all). The hippocampal and cortical MDA level was higher (p<0.001) while CAT, SOD, and total thiol were lower (p<0.01-p<0.001) in the Diabetic group than the Control. Treatment with 200 and 400 mg/kg Z. officinale extract reduced hippocampal and cortical MDA (p<0.001) and improved CAT (p<0.001) while, just the dose of 400 mg/kg of the extract increased SOD and total thiol in hippocampal and cortical tissues (p<0.001) compared with Diabetic group.
Conclusions:
Z. officinale extract could improve memory by reducing the oxidative stress in STZ-induced diabetes model.
Infection and inflammation are important pathological mechanism underlying neurodegenerative disorders and altered behavioral outcomes including learning and memory deficits. We tested the effect of agmatine in lipopolysaccharides (LPS)-induced learning and memory deficits in mice. Following 7 days of LPS administration animals were subjected to novel object recognition (NOR) test on day 8 and Morris water maze (MWM) test on days 9-13 for the assessment of its effect on learning and memory. Seven of days LPS treatment but not for 1 or 3 days, produced significant deficits in recognition and spatial memory in mice. In LPS pre-treated mice, agmatine treatment on day 8 resulted in the more exploration to the novel object. Agmatine treatment (day 8-12) in mice showed reduction in the escape latency and time spent in the target quadrant (probe trial) in the MWM test. However, co-administration of agmatine with LPS in mice for 7 days showed higher discrimination index in NOR test on Day-8. This co-administration also showed decrease in escape latency as well as time spent in the target quadrant in MWM test on days 9-13 as compared to LPS control group. Therefore, the results of this present study imply the protective and curative effects of agmatine against LPS mediated loss of memory functions in experimental animals.
• Highlights
• 1. Subchronic but not acute lipopolysaccharides induce memory deficits
• 2. Lipopolysaccharides impairs recognition and spatial memory in mice.
• 3. Agmatine prevents lipopolysaccharides-induced loss of memory.
• 4. Agmatine reverses deficits in learning and memory by lipopolysaccharides.
Background
β-Site APP-cleaving enzyme 1 (BACE1) is a key enzyme involved in the pathophysiology of Type 2 diabetes mellitus (T2DM) and mild cognitive impairment (MCI). We aimed to investigate the potential associations of plasma BACE1 levels and BACE1 gene polymorphism with different cognitive performances in T2DM patients with MCI.
Methods
The recruited 186 T2DM subjects were divided into 92 MCI group and 94 healthy-cognition controls, according to the Montreal Cognitive Assessment (MoCA) scores. Sociodemographic characteristics, clinical parameters and neuropsychological tests were assessed. BACE1 C786G gene polymorphism and plasma BACE1 level were determined.
Results
Compared to controls, MCI patients exhibited higher plasma BACE1 levels. Plasma BACE1 levels were negatively associated with MoCA, Clock Drawing Test and Logical Memory Test scores, whereas positively associated with Trail Making Test-B time in the MCI group (all p < 0.05), after adjusting fasting blood glucose, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance by C-peptide. Multivariable logistic regression analysis showed a significant trend towards increased MCI risk with high plasma BACE1 level in T2DM patients (OR = 1.492, p = 0.027). The plasma BACE1 levels of GG and GC genotypes were obviously higher than that of CC genotype in T2DM-MCI patients (p = 0.035; p = 0.026, respectively).
Conclusion
Increased plasma BACE1 levels were associated with poor overall cognition functions, especially visuospatial abilities, visual/logical memory and executive functions in T2DM-MCI patients. Additionally, elevated plasma BACE1 level was a risk factor for MCI in T2DM patients, and might be influenced by BACE1 C786G gene mutations.
Cannabidiol (CBD), a compound obtained from Cannabis sativa, has wide range of therapeutic properties, including mitigation of diabetes and neurodegeneration. Cerebral ischemia and consequent learning disabilities are aggravated in elderly diabetic subjects. However, there are no studies showing the effect of CBD treatment in elderly diabetes patients suffering cerebral ischemia. The present work tested the hypothesis that CBD treatment improves metabolic dysfunctions in middle-aged diabetic rats submitted to chronic cerebral hypoperfusion. In this work, 350-day-old male Wistar streptozotocin-induced diabetic rats were used. To induce cerebral ischemia was used a chronic cerebral hypoperfusion (CCH), surgically, via the four-vessel occlusion/internal carotid artery (4-VO/ICA). Four diabetic groups were established: Non-CCH Treated Diabetic (DNT), CCH Treated Diabetic (DCT), Non-CCH Vehicle Diabetic (DNV), and CCH Vehicle Diabetic (DCV). Vehicle groups were not treated with CBD. The animals were treated during 30 days with 10 mg CBD/Kg bw/day. After treatment, the animals were euthanized, and blood levels of glucose, insulin, total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, fructosamine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were evaluated. DCT group presented reduction of hyperglycemia and an increase of insulinemia. Also was observed lower fructosamine, LDL, HDL, triglycerides and total cholesterol levels. AST and ALT concentration were reduced in CBD treated groups. CBD may be used as therapeutic tool to protect metabolism against injuries from diabetes aggravated by cerebral ischemia.
The available medications for the treatment of major depressive disorder have limitations, particularly their limited efficacy, delayed therapeutic effects, and the side effects associated with treatment. These issues highlight the need for better therapeutic agents that provide more efficacious and faster effects for the management of this disorder. Ketamine, an N-methyl-D-aspartate receptor antagonist, is the prototype for novel glutamate-based antidepressants that has been shown to cause a rapid and sustained antidepressant effect even in severe refractory depressive patients. Considering the importance of these findings, several studies have been conducted to elucidate the molecular targets for ketamine’s effect. In addition, efforts are under way to characterize ketamine-like drugs. This review focuses particularly on evidence that endogenous glutamatergic neuromodulators may be able to modulate mood and to elicit fast antidepressant responses. Among these molecules, agmatine and creatine stand out as those with more published evidence of similarities with ketamine, but guanosine and ascorbic acid have also provided promising results. The possibility that these neuromodulators and ketamine have common neurobiological mechanisms, mainly the ability to activate mechanistic target of rapamycin and brain-derived neurotrophic factor signaling, and synthesis of synaptic proteins in the prefrontal cortex and/or hippocampus is presented and discussed.
Aims:
Oxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats.
Main methods:
Four groups were designed: sham control, agmatine-treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry.
Key findings:
The treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-γ, and IL-1α were brought back to the sham control levels by the treatment as well.
Significance:
Our findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress.
Diabetes comes with an additional burden of moderate to severe hyperlipidemia, but little is known about the effects of lipid-lowering therapy on diabetic complications such as diabetes-associated cognitive decline. Herein we investigated the effects of statins on memory impairment and neurotoxicity in streptozotocin (STZ)-induced diabetic mice. Our data indicated that oral administration of simvastatin at 10 or 20 mg/kg for 4 weeks significantly ameliorated diabetes-associated memory impairment reflected by performance better in the Morris water maze (MWM) and Y-maze tests. The further study showed that these treatments caused significant increase of peroxisome proliferator-activated receptor gamma (PPARγ) and decrease of NF-κB p65 in nucleus of hippocampus and cortex, and ameliorated neuroinflammatory response as evidenced by less Iba-1 positive cells and lower inflammatory mediators including IL-1β, IL-6 and TNF-α as well as suppressed neuronal apoptosis as indicated by decreased TUNEL-positive cells, increased ratio of Bcl-2/Bax and decreased caspase-3 activity in the hippocampus and cortex. Moreover, simvastatin pronouncedly attenuated amyloidogenesis by decreasing amyloid-β (Aβ), amyloid precursor protein (APP) and beta-site APP cleaving enzyme (BACE-1). As expected, treated with simvastatin, the diabetic mice exhibited significant improvement of hyperlipidemia rather than hyperglycemia. Our findings disclosed novel therapeutic potential of simvastatin for the diabetes-associated cognitive impairment.
Agmatine, a neurotransmitter/neuromodulator, has shown to exert numerous effects on the CNS. Chronic stress is a risk factor for development of depression, anxiety and deterioration of cognitive performance. Compelling evidences indicate an involvement of nitric oxide (NO) pathway in these disorders. Hence, investigation of the beneficial effects of agmatine on chronic unpredictable mild stress (CUMS)-induced depression, anxiety and cognitive performance with the involvement of nitrergic pathway was undertaken. Mice were subjected to a battery of stressors for 28 days. Agmatine (20 and 40 mg/kg, i.p.) alone and in combination with NO modulators like L-NAME (15 mg/kg, i.p.) and L-arginine (400 mg/kg i.p.) were administered daily. The results showed that 4-weeks CUMS produces significant depression and anxiety-like behaviour. Stressed mice have also shown a significant high serum corticosterone (CORT) and low BDNF level. Chronic treatment with agmatine produced significant antidepressant-like behaviour in forced swim test (FST) and sucrose preference test, whereas, anxiolytic-like behaviour in elevated plus maze (EPM) and open field test (OFT) with improved cognitive impairment in morris water maze (MWM). Furthermore, agmatine administration reduced the levels of acetylcholinesterase and oxidative stress markers. In addition, agmatine treatment significantly increased the BDNF level and inhibited serum CORT level in stressed mice. Treatment with L-NAME (15 mg/kg) potentiated the effect of agmatine whereas L-arginine abolished the anxiolytic, antidepressant and neuroprotective effects of agmatine. Agmatine showed marked effect on depression and anxiety-like behaviour in mice through nitrergic pathway, which may be related to modulation of oxidative–nitrergic stress, CORT and BDNF levels.
In this study, we investigated the effect of Dendropanax morbifera stem extract (DMS) on streptozotocin (STZ)-induced type 1 diabetic rats. The effect of DMS on memory function was assessed using the Morris water maze test. In addition, we investigated its effect on the microglial activation and subsequent release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in the hippocampus. Seven-week-old Wistar rats were exposed to 65 mg/kg STZ by intraperitoneal injection and 100 mg/kg of DMS was administered orally for 30 days. The administration of STZ significantly increased escape latency compared to the control group on all experimental days. Administration of DMS to STZ-treated rats significantly reduced the escape latency. Blood glucose levels significantly increased, while leptin levels significantly decreased in the STZ-treated rats compared to the control group. The administration of DMS to STZ-treated rats significantly ameliorated these changes in the levels of blood glucose and leptin. In addition, administration of DMS significantly increased the serum insulin levels in the STZ-treated rats, not in the control rats. Similarly, STZ treatment increased the morphological changes with hypertrophy of cytoplasm and processes in the hippocampal CA1 region, and significantly increased the levels of pro-inflammatory cytokines such as TNF-α and IL-1β levels in serum and hippocampal homogenates. Administration of DMS to STZ-treated rats significantly reduced the STZ-induced microglial activation and subsequent increase of TNF-α and IL-1β levels in the serum and hippocampal homogenates. These results indicate that DMS could prevent STZ-induced memory impairment by modulating the inflammatory responses in the hippocampus.
The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from l-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3β and the accumulation of Aβ and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal.
Experimental and clinical evidence indicates that pro-inflammatory cytokines, oxidative stress and brain-derived neurotrophic factor (BDNF) signalling mechanisms play a role in the pathophysiology of depression. Agmatine is a neurotransmitter and/or neuromodulator that has emerged as a potential agent to manage diverse central nervous system disorders. Agmatine has been shown to exert antidepressant-like effect. The present study investigated ability of agmatine to abolish the depressive-like behaviour induced by the administration of the lipopolysaccharide (LPS) in mice. Agmatine (20 and 40 mg/kg) was administered daily for 7 days, then the mice were challenged with saline or LPS (0.83 mg/kg; i.p.) on the 7th day. After 24 h of LPS administration we tested mice for depressive-like behaviour. LPS treated animals presented an increase in immobility time in the forced-swim test (FST), tail suspension test (TST) which was reversed by agmatine pre-treatment (20 and 40 mg/kg). Oxidative/nitrosative stress evoked by LPS was ameliorated by both doses of agmatine in hippocampus (HC) and prefrontal cortex (PFC). Administration of LPS caused an increase in interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), whereas BDNF was down regulated in the HC. Agmatine pre-treatment at 40 mg/kg ameliorated LPS-induced neuroinflammation by attenuating brain IL-1β and TNF-α level. In addition, agmatine pre-treatment also up-regulated the BDNF level in the HC. The present study shows that pre-treatment of agmatine is able to abolish the behavioural responses in the FST and TST elicited by the LPS-induced model of depression that may depend on the inhibition of pro-inflammatory mediators, reduction of oxidative stress as well as activation neuroplasticity-related signalling in mice, suggesting that agmatine may constitute an monotherapy/adjuvant for the management of depression associated with inflammation.
Diabetes is associated with impaired cognitive function. Streptozotocin (STZ)-induced diabetic rats exhibit a loss of neurogenesis
and deficits in behavioral tasks involving spatial learning and memory; thus, impaired adult hippocampal neurogenesis may
contribute to diabetes-associated cognitive deficits. Recent studies have demonstrated that adult neurogenesis generally occurs
in the dentate gyrus of the hippocampus, the subventricular zone, and the olfactory bulbs (OB) and is defective in patients
with diabetes. We hypothesized that OB neurogenesis and associated behaviors would be affected in diabetes. In this study,
we show that inhibition of Wnt3-induced neurogenesis in the OB causes several behavioral deficits in STZ-induced diabetic
rats, including impaired odor discrimination, cognitive dysfunction, and increased anxiety. Notably, the sodium- and chloride-dependent
GABA transporters (GATs) and excitatory amino acid transporters (EAATs) that localize to GABAergic and glutamatergic terminals
decreased in the OB of diabetic rats. Moreover, GAT1 inhibitor administration also hindered Wnt3-induced neurogenesis in vitro.
Collectively, these data suggest that STZ-induced diabetes adversely affects OB neurogenesis via GABA and glutamate transporter
systems, leading to functional impairments in olfactory performance.
Diabetes mellitus (DM) is related to an increase in the incidence of vascular dementia. Inflammation is an important cause of endothelial dysfunction and cognitive deficits. The anti-tumor necrosis factor (TNF)-α fusion protein etanercept has been reported to exhibit memory-enhancing effects and endothelial protection. We tested the effect of etanercept on the cognitive endpoints and compared it with the cognitive dysfunction in streptozotocin (STZ )-induced DM rats by using the Morris water maze test (MWMT) and passive avoidance test (PAT). Systolic blood pressure (SBP), thoracic endothelial function, endothelial nitric oxide synthase (eNOS) expression, and hippocampal brain-derived neurotrophic factor (BDNF) expression were assessed. Thirty days after the induction of DM, rats exhibited severe learning and memory deficits associated with endothelial dysfunction and decreased expression of eNOS and BDNF. Chronic treatment with etanercept (0.8 mg/kg, s.c., every week for 30 days) improved cognitive performance, endothelial function, and expression of eNOS and BDNF in DM rats. Furthermore, the memory-improving effects of etanercept were independent of hyperglycemia. These data suggest that etanercept treatment prevents changes in endothelial function, eNOS expression, and hippocampal expression of BDNF and, consequently, vascular dementia in DM rats.
Agmatine may act as a neurotransmitter or neuromodulator. Behaviorally, agmatine exerts antidepressant-like effects. The enzyme agmatinase degrades and thereby inactivates agmatine. The gene coding for human agmatinase is located on chromosome 1p36, a gene locus which has been linked to bipolar disorder and major depression. However, the enzyme has not yet been studied in detail in the context of neuropsychiatric diseases. We analyzed agmatinase protein expression in postmortem hippocampi of individuals with affective disorders. Agmatinase protein was detected in a subset of interneurons in the hippocampus and other brain regions. In depressive patients the number and the numerical density of agmatinase-immunopositive cell bodies was strongly elevated in all regions under study (i.e. hippocampus, habenula, insular cortex and temporal cortex). Agmatine is naturally produced by the breakdown of arginine. The cellular uptake of L-arginine and other cationic amino acids (such as L-lysine and L-ornithine) is mainly mediated by cationic amino acid transporter (CAT) proteins. In patients with mood disorder there was a circumscribed decrease in the numerical density of hCAT1 immunoreactive neurons in the CA2 region of the hippocampus.
The present study was undertaken to evaluate the effect of diosmin in diabetic neuropathy in type 2 diabetic rats.
Type 2 diabetes was induced in male Sprague-Dawley rats by single intraperitoneal injection of streptozotocin (35 mg/kg) and high-fat diet. Four weeks after the confirmation of diabetes, diabetic rats were treated with diosmin (50 and 100 mg/kg, p.o.) for next 4 weeks. Rats were evaluated for biochemical, behavioral and oxidative stress parameters. Eddy's hot plate and tail immersion test were performed on 6th, 7th, 8th, 9th and 10th weeks of experiment to assess thermal hyperalgesia and cold allodynia respectively. Further, the walking function test was performed for assessing the motor responses at the end of the treatment schedule.
Rats were fed with high-fat diet throughout the experiment schedule and administration of low-dose streptozotocin induced significant elevation in blood glucose level and insulin resistance which was confirmed by oral glucose tolerance test. Treatment with diosmin at doses of 50 and 100 mg/kg significantly restored the reduced body weight, elevated blood sugar and lipid profiles. Further the dose-dependent improvement was observed in thermal hyperalgesia, cold allodynia and walking function in diabetic rats treated with diosmin. Elevated levels of malondialdehyde, and nitric oxide and decreased glutathione levels and superoxide dismutase activity in diabetic rats were restored significantly after the 4 weeks of diosmin treatment.
Diosmin has shown beneficial effect in preventing the progression of early diabetic neuropathy in rats.
The aim of this work was to explore possible effects of agmatine, an endogenous inhibitor of inducible nitric oxide synthase (iNOS), against hypercholesterolemia-induced lipid profile changes and endothelial dysfunction.
Hypercholesterolemia was induced by feeding rabbits with a high-cholesterol diet (HCD, 0.5%) for 8 weeks. Another HCD-fed group was orally administered agmatine (10 mg/kg/day) during weeks 5 through 8. Serum lipid profile, malondialdehyde (MDA), nitric oxide (NO) and lactate dehydrogenase (LDH) were determined. Aorta was isolated to analyse vascular reactivity, atherosclerotic lesions and intima/media (I/M) ratio.
HCD induced a significant increase in serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). Agmatine administration significantly decreased HCD-induced elevations in serum TC and LDL-C, MDA, LDH and NO while significantly increased HDL-C levels. Additionally, agmatine significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to acetylcholine. HCD and agmatine did not significantly influence aortic endothelium-independent relaxation to sodium nitroprusside. Moreover, agmatine significantly reduced the elevation in aortic atherosclerotic lesion area and I/M ratio.
This study is the first to reveal that agmatine has the ability to ameliorate hypercholesterolemia-induced lipemic-oxidative and endothelial function injuries possibly by its antioxidant potential and/or iNOS inhibition.
Diabetic encephalopathy (DE) has been characterized by the impaired cognition and the abnormalities of neurochemistry and neurostructure. The study was conducted to evaluate the neuroprotective effect of paeonol on STZ-induced DE rats. Paeonol of 25, 50, 100mg/kg (p.o.) could decrease the latency time and path length, and enhance significantly the spent time in the target quadrant and platform crossings in Morris water maze test. The treatment with paeonol could also increase significantly Na(+)-K(+)-ATP enzyme and ChAT activities, as well as decreasing significantly AchE activity in hippocampal tissue. Immunohistochemistry and TUNEL staining showed that paeonol could attenuate apoptosis of neurons and caspase 3 expression, improve two neurotrophic factors BDNF and IGF expressions, and also ameliorate Aβ deposition in the hippocampus and cerebral cortex. In conclusion, the present study demonstrated diabetic rats treated with paeonol could ameliorate the cognition deficits. These findings indicated paeonol might act as a beneficial agent for the prevention and treatment of DE.
To study the analgesic effects of naringenin on chronic constriction injury (CCI) model of neuropathic pain.
After inducing of neuropathic pain by CCI, treatment with 25 and 50 mg/kg of naringenin and 10 mg/kg of pregabalin was given. Rats were evaluated for behavioral tests using Hargreaves apparatus for thermal hyperalgesia, pin prick test for tactile mechanical hyperalgesia and cold water-induced allodynia on days 0, 3, 5, 7, 14 and 21. At the end of study, oxidative stress parameters were measured.
Naringenin showed ameliorating action against CCI-induced neuropathic pain in all the tested models. Also, naringenin attenuated the elevated levels of lipid peroxidation and nitric oxide, and restored the level of reduced glutathione.
The results of the present investigation suggest that naringenin exhibits analgesic effect in sciatic nerve injury model.
Naringenin is a flavone flavonoid possessing antidiabetic, antioxidant and memory improving effects. Therefore, we studied the influence of naringenin against type-2 diabetes-induced memory dysfunction in rats. Type-2 diabetes was induced by high-fat diet and high-fat emulsion for two weeks and a low dose of streptozotocin (35 mg/kg). The memory deficit was assessed by using a novel object recognition paradigm. The changes in oxidative markers and cholinesterase (ChE) levels were evaluated in the hippocampal region. After confirmation of diabetes, naringenin (50 mg/kg) treatment was given to animals as a preventive and in another set of experiments naringenin (25 and 50 mg/kg) or pioglitazone (5 mg/kg) or donepezil (3 mg/kg) treatments were started after long-standing diabetes (4 weeks after confirmation). Both the treatment schedules show significant protection and improvement in cognitive behavior against diabetes-induced memory dysfunction and biochemical changes. Also, treatment with pioglitazone and donepezil improved memory performance in rats. Naringenin was found to decrease oxidative stress by depleting elevated lipid peroxide and nitric oxide and elevating reduced glutathione levels. Cholinergic function was improved by naringenin through the inhibition of elevated ChE activity. In conclusion, the present study suggests that naringenin acts as an antioxidant and ChE inhibitor against type-2 diabetes-induced memory dysfunction.
A polyamine agmatine is produced through decarboxylation of L -arginine by the enzyme arginine decarboxylase and is a new neurotransmitter in central nervous system (CNS). It has been suggested that agmatine has analgesic, anxiolytic and antidepressant activities in animals. In experimental studies, it also generates some favorable effects on cerebral damages and withdrawal syndromes involved in addictive drugs. Furthermore, it modulates some processes of learning and memory. Thus, agmatine may be an important target for the treatment of CNS disorders. However, the abnormal release and transmission of agmatine in brain may also be related to some CNS disorders, such as schizophrenia. Interaction of agmatine with other central neurotransmitter systems, such as the glutamatergic and nitrergic systems, seems to be very important. According to the current literature, we can expect that the central agmatinergic system may be a new key target in development of novel approaches for understanding the etiopathogenesis of CNS disorders and their treatment with drugs. The main goal of this article is to evaluate the effects of agmatine in CNS and underline its pharmacological actions in CNS and drug development.
Agmatine is an endogenous neuromodulator that, based on animal studies, has the potential for new drug development. As an endogenous aminoguanidine compound (1-amino-4-guanidinobutane), it is structurally unique compared with other monoamines. Agmatine was long thought to be synthesised only in lower life forms, until its biosynthetic pathway (decarboxylation of arginine) was described in the mammalian brain in 1994. Human arginine decarboxylase has been cloned and shown to have 48% identity to ornithine decarboxylase. In neurons of the brain and spinal cord, agmatine is packaged into synaptic vesicles and released upon neuronal depolarisation. Other evidence of a neuromodulation role for agmatine is the presence of a specific cellular uptake mechanism and a specific metabolic enzyme (agmatinase; which forms putrescine).
Initially, agmatine was conceptualised as an endogenous clonidine-displacing substance of imidazoline receptors; however, it has now been established to have affinity for several transmembrane receptors, such as α2-adrenergic, imidazoline I1 and glutamatergic NMDA receptors. In addition to activity at these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase and downregulates inducible nitric oxide synthase.
Endogenous agmatine is induced in response to stress and/or inflammation. Stressful conditions that induce agmatine include hypoxic-ischaemia and cold-restraint stress of ulcerogenic proportion. Induction of agmatine in the brain seems to occur in astrocytes, although neurons also synthesise agmatine. The effects of injected agmatine in animals include anticonvulsant-, antineurotoxic- and antidepressant-like actions. Intraperitoneal or intracerebroventricular injections of agmatine rapidly elicit antidepressant-like behavioural changes in the rodent forced swim test and tail suspension test. Intraperitoneal injections of agmatine into rats and mice also elicit acute anxiolytic-like behavioural changes in the elevated plus-maze stress test. In an animal model of acute stress disorder, intraperitoneal agmatine injections diminish contextual fear learning. Furthermore, intraperitoneal injections of agmatine reduce alcohol and opioid dependence by diminishing behaviour in a rat conditioned place preference paradigm.
Based on these findings, agmatine appears to be an endogenous neuromodulator of mental stress. The possible roles and/or beneficial effects of agmatine in stress-related disorders, such as depression, anxiety and post-traumatic stress disorder, merit further investigation.
To elucidate the influence of oxidative stress on the brain functions during aging, the cognitive performance ability of rats was assessed by using the water-maze test as an oxidative stress before and after hyperoxia. Young rats showed significantly greater learning ability than both old rats and vitamin-E-deficient rats. Although the memory functions of all rats were impaired after oxidative stress, the memory retention of young rats was greater than those of other groups. After the stress, none of the rats recovered their learning ability. During aging and through hyperoxia, the release of acetylcholine from nerve terminals was remarkably decreased. Instead, thiobarbituric acid reactive substance (TBARS) contents in rat hippocampus and cebral cortex, and their synaptic membranes, were significantly increased during aging and by oxidative stress. The antioxidative defense system in rat brain was also changed by the stress. These results suggest that oxidative stress may contribute to learning and memory deficits following oxidative brain damage during aging.
Agmatine is an endogenous neuromodulator with potential for new drug development based on animal studies. As an endogenous aminoguanidine compound (1-amino-4-guanidinobutane), it is structurally unique compared to other monoamines. Agmatine was long thought to be synthesized only in lower life forms until its biosynthetic pathway (decarboxylation of arginine) was described in the brain in 1994. By now, a human arginine decarboxylase has been cloned and shown to be an enzyme with 48% identity to ornithine decarboxylase. In neurons of the brain and spinal cord, agmatine is packaged into synaptic vesicles and released upon depolarization; there is a specific cellular uptake mechanism. The main metabolic product of agmatine, putrescine, is formed by agmatinase (ureohydrolase). Initially, agmatine was conceptualized as an endogenous clonidine-displacing substance of imidazoline receptors. However, it is now established that it has affinity for several transmembrane receptors, such as α2-adrenergic, imidazoline-1, and NMDA-glutamatergic receptors. Besides its activity through these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase (nNOS) and down-regulates inducible nitric oxide synthase (iNOS). Endogenous agmatine is also induced in response to various stressors and/or inflammation. Stressful conditions that have been shown to induce agmatine include hypoxic-ischemia and cold-restraint stress of ulcerogenic proportion. Brain inductions of agmatine seem to occur in astrocytes, although neurons also synthesize agmatine. In other studies, the effects of injected agmatine have included anti-convulsant, anti-neurotoxic, and antidepressant-like actions. For instance, injections of agmatine can rapidly elicit antidepressant-like behavioral changes in the forced swim test and tail suspension test. Agmatine injections into rats and mice also elicit acute anxiolytic-like behavioral changes in the elevated plus maze stress test. In an animal model of acute stress disorder, agmatine injections diminish contextual fear learning. Furthermore, injections of agmatine reduce alcohol and opioid dependence by diminishing dependence on morphine in a rat conditioned place preference paradigm. Based on these findings, the hypothesis has emerged that agmatine is an endogenous neuromodulator of mental stress. Agmatine’s possible role and/or beneficial effects in stress-related disorders, such as depression, anxiety and posttraumatic stress disorder, merits further investigation.
Diabetes mellitus is a metabolic disorder associated with structural and functional alterations of various organ systems including the central nervous system. The aim of present study was to investigate the neuroprotective effect of agmatine (AGM) on cerebral ischemic damage in diabetic rats.
Normoglycemic (n=30) and streptozocine-induced diabetic rats (n=82) were subjected to 30 minutes of suture-occlusion of the middle cerebral artery (MCAO) with 24 or 72 hours of reperfusion. Thirty-nine diabetic rats were treated with AGM (100 mg/kg, intraperitoneal) immediately after 30 minutes of MCAO. To evaluate the motor function, a modified neurological examination and rota-rod exercise were performed. The brain infarct volume and edema volume were assessed. Caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining were used to evaluate cellular apoptosis. Western blot and immunohistochemical analysis were performed to determine the expression of neuronal nitric oxide synthase (NOS) and inducible NOS in ischemic brain tissues.
AGM posttreatment improved the neurobehavioral activity of diabetic MCAO rats at 24 and 72 hours after reperfusion. The infarct size and edema volume were reduced in AGM-treated diabetic rats compared with those in diabetic rats without AGM posttreatment (P<0.01). Immunohistochemical analysis showed that AGM treatment significantly decreased the number of caspase-3-positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells in diabetic MCAO rats at 24 and 72 hours after reperfusion (P<0.01). Western blotting and immunohistochemistry results indicated that AGM treatment significantly decreased neuronal NOS and inducible NOS expression in diabetic rats at 24 and 72 hours after reperfusion (all P<0.05).
AGM posttreatment reduced cerebral infarct size and neurological deficit expression in diabetic rats subjected to MCAO. The reduced infarct size was associated with a decrease in apoptosis and NOS expression.
J. Neurochem. (2011) 116, 67–75.
Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in the CNS in several models of cellular damage. However, the mechanisms involved in these protective effects in neurodegenerative diseases are poorly understood. The present study was undertaken to investigate the effects of agmatine on cell injury induced by rotenone, commonly used in establishing in vivo and in vitro models of Parkinson’s disease, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report that agmatine dose-dependently suppressed rotenone-induced cellular injury through a reduction of oxidative stress. Similar effects were obtained by spermine, suggesting a scavenging effect for these compounds. However, unlike spermine, agmatine also prevented rotenone-induced nuclear factor-κB nuclear translocation and mitochondrial membrane potential dissipation. Furthermore, rotenone-induced increase in apoptotic markers, such as caspase 3 activity, Bax expression and cytochrome c release, was significantly attenuated with agmatine treatment. These findings demonstrate mitochondrial preservation with agmatine in a rotenone model of apoptotic cell death, and that the neuroprotective action of agmatine appears because of suppressing apoptotic signalling mechanisms. Thus, agmatine may have therapeutic potential in the treatment of Parkinson’s disease by protecting dopaminergic neurons.
People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.
This was a cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.
In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).
High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes.
The arginine metabolite agmatine is able to protect brain mitochondria against the drop in energy capacity by the Ca(2+)-dependent induction of permeability transition (MPT) in rat brain mitochondria. At normal levels, the amine maintains the respiratory control index and ADP/O ratio and prevents mitochondrial colloid-osmotic swelling and any electrical potential (DeltaPsi) drop. MPT is due to oxidative stress induced by the interaction of Ca(2+) with the mitochondrial membrane, leading to the production of hydrogen peroxide and, subsequently, other reactive oxygen species (ROS) such as hydroxyl radicals. This production of ROS induces oxidation of sulfhydryl groups, in particular those of two critical cysteines, most probably located on adenine nucleotide translocase, and also oxidation of pyridine nucleotides, resulting in transition pore opening. The protective effect of agmatine is attributable to a scavenging effect on the most toxic ROS, i.e., the hydroxyl radical, thus preventing oxidative stress and consequent bioenergetic collapse.
In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis.
We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis.
Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P < 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P < 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P < 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P < 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia.
This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.
Type 1 diabetes is a common metabolic disorder accompanied by an increased secretion of glucocorticoids and cognitive deficits. Chronic excess of glucocorticoids per se can evoke similar neuropathological signals linked to its major target in the brain, the hippocampus. This deleterious action exerted by excess adrenal stress hormone is mediated by glucocorticoid receptors (GRs). The aim of the present study was to assess whether excessive stimulation of GR is causal to compromised neuronal viability and cognitive performance associated with the hippocampal function of the diabetic mice. For this purpose, mice had type 1 diabetes induced by streptozotocin (STZ) administration (170 mg/kg, i.p.). After 11 days, these STZ-diabetic mice showed increased glucocorticoid secretion and hippocampal alterations characterized by: (1) increased glial fibrillary acidic protein-positive astrocytes as a marker reacting to neurodegeneration, (2) increased c-Jun expression marking neuronal activation, (3) reduced Ki-67 immunostaining indicating decreased cell proliferation. At the same time, mild cognitive deficits became obvious in the novel object-placement recognition task. After 6 days of diabetes the GR antagonist mifepristone (RU486) was administered twice daily for 4 days (200 mg/kg, p.o.). Blockade of GR during early type 1 diabetes attenuated the morphological signs of hippocampal aberrations and rescued the diabetic mice from the cognitive deficits. We conclude that hippocampal disruption and cognitive impairment at the early stage of diabetes are caused by excessive GR activation due to hypercorticism. These signs of neurodegeneration can be prevented and/or reversed by GR blockade with mifepristone.
Alzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid beta-amyloid peptide (beta AP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic beta AP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble beta AP in these in vitro assays is enhanced by addition of small amounts of pre-aggregated beta-amyloid "seed" material. We also have prepared these seeds by using a naturally occurring reaction between glucose and protein amino groups resulting in the formation of advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified beta AP-nucleation seeds further accelerated aggregation of soluble beta AP compared to non-modified "seed" material. Over time, nonenzymatic advanced glycation also results in the gradual accumulation of a set of posttranslational covalent adducts on long-lived proteins in vivo. In a standardized competitive ELISA, plaque fractions of AD brains were found to contain about 3-fold more AGE adducts per mg of protein than preparations from healthy, age-matched controls. These results suggest that the in vivo half-life of beta-amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid.
Moderate impairment of learning and memory has been recognized as a complication of diabetes. The present study examined behavioral and electrophysiological measures of cerebral function in streptozotocin (STZ)-induced diabetic rats. Behavioral testing consisted of a spatial learning task in a water maze. Electrophysiological testing consisted of in vitro assessment of hippocampal long-term potentiation (LTP), an activity-dependent form of synaptic plasticity, which is believed to be related to the cellular mechanisms of learning and memory. Two experiments were performed: the first with severely hyperglycemic rats and the second with moderately hyperglycemic rats. Rats were tested in the water maze 11 weeks after induction of diabetes. Next, LTP was measured in vitro in trained animals. Both spatial learning and LTP expression in the CA1 field of the hippocampus were impaired in severely hyperglycemic rats as compared with nondiabetic controls. In contrast, spatial learning and hippocampal LTP were unaffected in moderately hyperglycemic rats. The association of alterations in hippocampal LTP with specific learning impairments has previously been reported in conditions other than diabetes. Our findings suggest that changes in LTP-like forms of synaptic plasticity in the hippocampus, and possibly in other cerebral structures, are involved in learning deficits in STZ-induced diabetes. The beneficial effect of moderate glycemic control on both place learning and hippocampal LTP supports the significance of the relation between these two parameters and indicates that the development of the observed deficits may be related to the level of glycemic control.
The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.
Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves. Vascular endothelial cells are an important target of hyperglycaemic damage, but the mechanisms underlying this damage are not fully understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms; increased formation of glucose-derived advanced glycation end-products; and increased glucose flux through the aldose reductase pathway. The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities. Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells. Here we show that this increase in reactive oxygen species is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing levels of mitochondrial reactive oxygen species with each of these agents prevents glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation and NFkappaB activation.
Diabetes mellitus leads to functional and structural changes in the brain which appear to be most pronounced in the elderly. Because the pathogenesis of brain ageing and that of diabetic complications show close analogies, it is hypothesized that the effects of diabetes and ageing on the brain interact. Our study examined the effects of diabetes and ageing on learning and hippocampal synaptic plasticity in rats.
Young adult (5 months) and aged (2 years) rats were examined after 8 weeks of streptozotocin-diabetes. Learning was tested in a Morris water maze. Synaptic plasticity was tested ex vivo, in hippocampal slices, in response to trains of stimuli of different frequency (0.05 to 100 Hz).
Statistically significant learning impairments were observed in young adult diabetic rats compared with controls. These impairments were even greater in aged diabetic animals. In hippocampal slices from young adult diabetic animals long-term potentiation induced by 100 Hz stimulation was impaired compared with controls (138 vs 218% of baseline). In contrast, long-term depression induced by 1 Hz stimulation was enhanced in slices from diabetic rats compared with controls (79 vs 92%). In non-diabetic aged rats synaptic responses were 149 and 93% of baseline in response to 100 and 1 Hz stimulation, compared with 106 and 75% in aged diabetic rats.
Both diabetes and ageing affect learning and hippocampal synaptic plasticity. The cumulative deficits in learning and synaptic plasticity in aged diabetic rats indicate that the effects of diabetes and ageing on the brain could interact.
Activation of imidazoline I2 receptor (I2R) by agmatine in adrenal gland lowers plasma glucose through increment in β-endorphin release to stimulate the opioid μ-receptor in streptozotocin-induced diabetic rats (STZ rats). However, the subtype of I2R for agmatine-induced blood glucose lowering effect remains obscure. In the present study, agmatine treatment increased β-endorphin secretion and this effect was blocked by I2R antagonist (BU224) in the isolated adrenal medulla. We further used amiloride, an established blocker of I2AR, to identify the subtype of I2R in adrenal gland. Results showed that agmatine-induced β-endorphin release from adrenal gland was blocked by 0.1μM amiloride indicating the mediation of I2AR. It was further confirmed that agmatine-induced plasma glucose decrement and plasma β-endorphin increment in STZ rats were blocked by amiloride. However, amiloride failed to modify the action of guanidine, an agonist of I2BR, at the sufficient dose to block β-endorphin secretion. Taken together, the increase of plasma β-endorphin by agmatine in STZ rats through activation of imidazoline I2R was mainly induced by the I2A subtype located in adrenal gland. Thus, imidazoline I2A receptor in the adrenal gland might be applied as a new target for induction of opioid secretion.
Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits are paralleled by neurophysiological and structural changes in the brain. In animal models of diabetes, impairments of spatial learning occur in association with distinct changes in hippocampal synaptic plasticity. At the molecular level these impairments might involve changes in glutamate-receptor subtypes, in second-messenger systems and in protein kinases. The multifactorial pathogenesis of diabetic encephalopathy is not yet completely understood, but clearly shares features with brain ageing and the pathogenesis of diabetic neuropathy. It involves both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. Treatment with insulin might therefore not only correct hyperglycaemia, but could also directly affect the brain.
Diabetes and normal aging are both characterized by increases in levels of glucocorticoids. Because long-term exposure to elevated glucocorticoids can be detrimental to hippocampal function, we evaluated the performance of young diabetic rats in the 14-unit T-maze, a task that is sensitive to hippocampal deficits. To assess the contribution of diabetes-induced elevations in corticosterone levels, we examined maze learning in diabetic rats that had levels of corticosterone ‘clamped’ through adrenalectomy and low-dose corticosterone replacement. For comparison, we also tested a separate group of young and aged rats in the maze. Adrenally intact diabetic rats learned poorly in the 14-unit T-maze. Preventing the increases in corticosterone levels that accompanies the onset of experimental diabetes also prevented deficits in complex maze learning. The pattern of errors made by adrenally intact diabetic rats was similar to the pattern of errors made by aged rats, suggesting that the cognitive profiles of diabetic and aged rats share common features.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Both acetylcholine and glutamate are now thought to play important roles in memory. Recent evidence suggests that the interaction of these two neurotransmitters may be important for some forms of memory, and that acetylcholine, in particular, may function to facilitate glutamate activity by coordinating states of acquisition and recall in the cortex and hippocampus.
The present study systematically investigated the effects of agmatine administered i.p. in several commonly used behavioral tasks. In Experiment 1, pre-test treatment of agmatine (1 and 40 mg/kg) appeared to improve animals' performance in the water maze probe test conducted 24 h, but not 120 s, after training, when the effect was evaluated within subjects. In Experiment 2, pre-test agmatine treatment (40 mg/kg) did not affect animals' performance in the open field, and the place navigation, probe tests (1–4 and 6), reversal test and cued navigation in the water maze, but significantly facilitated performance in probe 5 which was conducted 96 h after training. In Experiment 3, rats with pre-test agmatine treatment (40 mg/kg) were less anxious relative to the controls, with no performance changes in the open field. In the water maze task, post-training agmatine treatment (40 mg/kg) did not affect place and cued navigation, but significantly improved animals' performance in the probe test conducted 24 h after training and the reversal test. In the working memory version of the task, agmatine treated rats took significantly less time and generated markedly shorter path length to reach the platform at the 180 s, but not 30 s, delay relative to the controls. In the object recognition task, rats with pre-test agmatine treatment (40 mg/kg) spent significantly more time exploring displaced objects, but not novel object, as compared to the controls. In Experiment 4, pre-test agmatine treatment (40 mg/kg) had no effect on the task acquisition in the delayed non-match to position task in the T-maze, but significantly facilitated performance at the 600 s delay. These results suggest that the behavioral effects of agmatine are task- and delay-dependent, and agmatine facilitates memory particularly when the task difficulty is increased due to memory trace decay and/or greater interference.
A water-soluble (at pH 8) aromatic disulfide [5,5'-dithiobis(2-nitrobenzoic acid)] has been synthesized and shown to be useful for determination of sulfhydryl groups. Several applications have been made to show its usefulness for biological materials. A study of the reaction of this disulfide with blood has produced some evidence for the splitting of disulfide bonds by reduced heme.
It is increasingly recognized that diabetes mellitus can lead to long-term complications in the brain. Clinically, these complications are manifested in alterations in cognitive functioning. This paper offers an overview on the impact of diabetes on cognition and provides leads for the evaluation and management of cognitive disturbances in patients with diabetes in a primary care setting. The main message is that while some patient groups appear to be at increased risk of cognitive impairments, in the majority of patients diabetes is not associated with the development cognitive decrements that would be regarded as clinically relevant. Frank impairments of cognition mainly occur in patients above the age of 65, often in association with vascular co-morbidity. Other groups at risk for cognitive decrements are children with an early age at diabetes onset and patients with clinically manifest retinopathy or other microvascular complications. No specific treatment options are available, but for now treatment of vascular risk factors and attention for glycaemic control appears to be a logical approach. Given the recent progress in this field, new treatments to prevent cognitive impairment in patients with diabetes may hopefully become available in the near future.
Memory impairment induced by streptozotocin in rats is a consequence of changes in CNS that are secondary to chronic hyperglycemia, impaired oxidative stress, cholinergic dysfunction, and changes in glucagon-like peptide (GLP). Treatment with antihyperglycemics, antioxidants, and cholinergic agonists are reported to produce beneficial effect in this model. Berberine, an isoquinoline alkaloid is reported to exhibit anti-diabetic and antioxidant effect, acetylcholinesterase (AChE) inhibitor, and increases GLP release. However, no report is available on influence of berberine on streptozotocin-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., twice daily, 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. In another set of experiment, berberine (100mg/kg) treatment during training trials also improved learning and memory, lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C or metformin, and donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or choline esterase activity. In conclusion, the present study demonstrates treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in diabetic rats.
The current study characterizes fear conditioning responses following global ischemia and evaluates neuronal damage affecting discrete extra-hippocampal areas susceptible to contribute to post ischemic emotional and memory impairments. Conditioned emotional response, Barnes Maze and object recognition tests were used to assess emotional, spatial and recognition memory, respectively. Behavioural testing was initiated in middle-aged animals (10-12 month old) 1 week following sham (n=16) or 4VO occlusion (n=18). Post-mortem cellular assessment was performed in the hippocampal CA1 layer, the perirhinal cortex and basolateral amygdala. Middle-aged ischemic animals showed impaired spatial memory in the initial three testing days in the Barnes Maze and deficit in recognition memory. Of interest, ischemic rats demonstrated a significant reduction of freezing and increased locomotion during the contextual fear testing period, suggesting reduced fear in these animals. Assessment of neuronal density 40 days following global ischemia revealed that CA1 neuronal injury was accompanied by 20-25% neuronal loss in the basolateral nucleus of the amygdala and perirhinal cortex in middle-aged ischemic compared to sham-operated animals. This study represents the first demonstration of altered conditioned fear responses following ischemia. Our findings also indicate a vulnerability of extra-hippocampal neurons to ischemic injury, possibly contributing to discrete emotional and/or memory impairments post ischemia.
Metformin is widely used in clinic for handling the diabetic disorders. However, action mechanisms of metformin remain obscure. It has recently been indicated that guanidinium derivatives are ligands to activate type-2 imidazoline receptors (I-2 receptors) that can improve diabetes through increment in skeletal muscle glucose uptake. Also, activation of I-2 receptors can increase the release of ß-endorphin in diabetic animals. Because metformin is a guanidinium derivative, we were interested in the effect of metformin on I-2 receptors. In the present study, the marked blood glucose-lowering action of metformin in streptozotocin-induced type-1 like diabetes rats was blocked by specific I-2 receptor antagonist, BU224, in a dose-dependent manner. Also, the increase of ß-endorphin release by metformin was blocked by BU224 in same manner. A specific competition between metformin and BU224 was observed in isolated adrenal medulla. Otherwise, amiloride at the dose sufficient to block I-2A receptor abolished the metformin-induced ß-endorphin release, but only the blood glucose-lowering action of metformin was markedly reduced. In addition, the blood glucose-lowering action of metformin in bilateral adrenalectomized rats was diminished by amiloride at higher doses. These results suggest that metformin might activate imidazoline I-2 receptors while I-2A receptors link the increase of ß-endorphin release and I-2B receptors couple to the other actions for lowering of blood glucose in type-1 like diabetic rats.
Studies have shown that an enriched environmental (EE) enhances hippocampal neurogenesis and dendritic branching in rodents, improving the performance in learning and memory task. Diabetes, however, is associated with memory deficits and decreasing in cell proliferation in the hippocampal dentate gyrus (DG), possibly related with higher glucocorticoid levels. Thus, our objective was to investigate the influence of EE on the memory deficits and cell proliferation of diabetic rats. For this, we reared rats for 2 months during early stages of life in standard environments (control rats) or EE. At adulthood, control and EE groups were divided and half of them induced to diabetes by a single injection of streptozotocin, 60 mg/kg, via i.p. Memory deficit was evaluated in these groups in the novel object-placement recognition task 11 days after diabetes induction. BrdU label cells were detected by immunohistochemistry after 3 days of administration to correlate cell proliferation in the DG area and performance in the memory task. Our results showed that EE decreased memory deficits in diabetic-induced rats (p < 0.05). Although cell proliferation in the DG was lower in the diabetic rats, enriched environment did not interfere in this parameter. These findings suggest that enriched environment is able to prevent or delay the development of memory deficits caused by diabetes in rats.
The effect of agmatine on memory formation in morphine-treated mice on the step-down inhibitory avoidance test was examined. Pre-training and pre-test administration of agmatine (5, 10 and 20mg/kg, s.c.) facilitated memory formation and retrieval while post-training administration of agmatine (5, 10 and 20mg/kg, s.c.) had no effect on memory consolidation. Idazoxan (5mg/kg, i.p.) inhibited the effect of agmatine on memory formation and retrieval. Pre-training administration of morphine (1.25, 2.5 and 5mg/kg, s.c.) impaired memory formation while post-training and pre-test administration of morphine (1.25, 2.5 and 5mg/kg, s.c.) had no effect on memory consolidation and retrieval. Pre-training agmatine treatment reversed the impairment of morphine on memory formation. Moreover, pre-test administration of agmatine inhibited morphine-induced amnesia. Pre-training and pre-test idazoxan (5mg/kg, i.p.) treatment inhibited the effect of agmatine on morphine induced memory impairment. In conclusion, agmatine inhibited morphine-induced memory impairment on the mice step-down inhibitory avoidance test. The mechanism was exerted, at least in part, through activation of imidazoline receptors.
Diabetes-related cognitive dysfunction is a consequence of changes within the central nervous system that are secondary to chronic hyperglycemia, oxidative stress, and cholinergic dysfunction, and probably therefore anti-diabetics, anti-oxidants, and acetylcholine esterase (AChE) inhibitors were found to have beneficial effects in animal models. Quercetin, a bioflavonoid widely distributed in the plants is reported to be a potent anti-diabetic, anti-oxidant, AChE inhibitor, and memory enhancer. Therefore, we screened its influence against diabetes-induced cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water and elevated plus maze (EPM) paradigms. Thirty days after diabetes induction rats exhibited marked and persistent hyperglycemia, weight loss, higher escape latency during training trials and reduced time spent in target quadrant in probe trial in Morris water maze test, and increased escape latency in EPM task. Treatment with quercetin (5-20 mg/kg, p.o., twice daily, 30 days) in streptozotocin-induced diabetic rats prevented the changes in blood glucose, body weight, and performance in Morris water and elevated plus maze tasks. In another set of experiment, quercetin (40 mg/kg, p.o., twice daily) treatment during training trials (31-35 days) markedly decreased escape latency and increased time spent in target quadrant during Morris water maze task. This treatment also decreased blood glucose levels, but had no influence on body weights. These effects were comparable to vitamin C (100 mg/kg, twice daily, 30 days) and donepezil (3 mg/kg day 31-day 35, during training trials), and devoid of any motor deficit and anxiety-like effect when tested in open field test. In conclusion, quercetin may provide a new potential option for prevention of the cognitive dysfunction in diabetes.
This study investigated whether exacerbation of poststroke dementia by diabetes associated abnormal tau phosphorylation and its mechanism. Streptozotocin (STZ) injection and/or a high fat diet (HFD) were used to treat rats to induce type 1 and 2 diabetes. Animals were randomly divided into STZ, HFD, STZ-HFD, and normal diet (NPD) groups. Focal ischemic stroke was induced by middle cerebral artery occlusion (MCAO). Cognitive function was tested by the Morris water maze. STZ or STZ-HFD treatment exacerbated ischemia-induced cognitive deficits, brain infarction and reduction of synaptophysin expression. Moreover, we found that diabetes further increased AT8, a marker of hyperphosphorylated tau, protein and immunopositive stained cells in the hippocampus of rats following MCAO while reduced the level of phosphorylated glycogen synthase kinase 3-beta at serine-9 residues (p-ser9-GSK-3beta), indicating activation of GSK-3beta. We conclude that diabetes further deteriorates ischemia-induced brain damage and cognitive deficits which may be associated with abnormal phosphorylation of tau as well as activation of GSK-3beta. These findings may be helpful for developing new strategies to prevent/delay formation of poststroke dementia in patients with diabetes.
Neuroinflammation is associated with a number of neurodegenerative diseases. It is known that lipopolysaccharide (LPS) treatment induces neuroinflammation and memory deterioration. Agmatine, the metabolite of arginine by arginine decarboxylase, is suggested to be a neuroprotective agent. The aim of this study was to explore if agmatine can prevent LPS-induced spatial memory impairment and hippocampal apoptosis. Adult male Wistar rats (200-250 g) were trained in water maze for 4 days (3 days in hidden platform and the last day in visible platform task). Saline, LPS (250 microg/kg/ip) or (and) agmatine (5 or 10 mg/kg) were administered 4h before every training session. LPS treatment impaired water maze place learning while agmatine co-administration prevented it. Also western blot studies revealed that LPS induces hippocampal caspase-3 activation while agmatine treatment prevented it.
Learning and memory deficits occur in diabetes mellitus. Although the pathogenesis of cognitive impairment in diabetes has not been fully elucidated, factors such as metabolic impairments, vascular complications and oxidative stress are thought to play possible roles. Here we investigated the effect of chronic treatment with vitamin C (50mg/kg, p.o), vitamin E (100mg/kg, p.o) and both together on passive avoidance learning (PAL) and memory in male Wistar control and diabetic rats. Treatments were begun at the onset of hyperglycemia. Passive avoidance learning was assessed 30 days later. Retention was tested 24h after training. At the end, animals were weighed and blood samples were drawn for plasma glucose measurement. Diabetes caused impairment in acquisition and retrieval processes of PAL and memory. The combination of vitamin C and E improved learning and memory in controls and reversed learning and memory deficits in diabetic rats. Combined treatment also affected the body weight and plasma glucose level of diabetic treated animals compared to untreated diabetic animals. Hypoglycemic effects and antioxidant properties of the vitamins may be involved in the nootropic effect of such treatment. These results show that combined treatment with vitamins C and E improved PAL and memory of control rats. In addition, combined vitamins administration to rats for 30 days from onset of diabetes alleviated the negative influence of diabetes on learning and memory. Therefore, combined vitamins treatment may provide a new potential alternative for prevention of impaired cognitive functions associated with diabetes and may warrant further clinical study.
An increased activity of the hypothalamo-pituitary-adrenal axis resulting in exaggerated glucocorticoid secretion has been repeatedly described in patients with diabetes mellitus and in animal models of this disease. However, it has been pointed out that experimental diabetes is accompanied by a decreased glucocorticoid response to ACTH stimulation. Because previous studies from our laboratory demonstrate the involvement of nitric oxide (NO) in the modulation of corticosterone production, present investigations were designed to evaluate 1) the impact of streptozotocin (STZ)-induced diabetes on the adrenocortical nitrergic system and 2) the role of NO in the modulation of adrenal steroidogenesis in STZ-diabetic rats. Four weeks after STZ injection, increased activity and expression levels of proteins involved in L-arginine transport and in NO synthesis were detected, and increased levels of thiobarbituric acid reactive species, carbonyl adducts, and nitrotyrosine-modified proteins were measured in the adrenocortical tissue of hyperglycemic rats. An impaired corticosterone response to ACTH was evident both in vivo and in adrenocortical cells isolated from STZ-treated animals. Inhibition of NO synthase activity resulted in higher corticosterone generation in adrenal tissue from STZ-treated rats. Moreover, a stronger inhibition of steroid output from adrenal cells by a NO donor was observed in adrenocortical Y1 cells previously subjected to high glucose (30 mM) treatment. In summary, results presented herein indicate an inhibitory effect of endogenously generated NO on steroid production, probably potentiated by hyperglycemia-induced oxidative stress, in the adrenal cortex of STZ-treated rats.
The medial temporal lobe plays a critical role in recognition memory but, within the medial temporal lobe, the precise neural structures underlying recognition memory remain equivocal. In this study, visual paired comparison (VPC) was used to investigate recognition memory in a human patient (YR), who had a discrete lesion of the hippocampus, and a group of monkeys with neonatal hippocampal lesions, which included the dentate gyrus, and a portion of parahippocampal region. Participants were required to view a picture of an object on a coloured background. Immediately afterwards, this familiar object was shown again, this time paired with a novel object. All participants displayed a novelty preference, provided the background on which the objects were shown was the same as the one used during the learning phase. When the background of the familiar object was changed between initial familiarization and test, only the control subjects showed a novelty preference; the hippocampal-lesioned monkeys and patient YR showed null preference. The results are interpreted within Eichenbaum and Bunsey's [Eichenbaum, H., & Bunsey, M. (1995). On the binding of associations in memory: Clues from studies on the role of the hippocampal region in paired-associate learning. Current Directions in Psychological Science, 4, 19-23] proposal that the hippocampus facilitates the formation of a flexible representation of the elements that make up a stimulus whereas the parahippocampal region is involved in the formation of a fused representation.
Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with increased oxidative stress in the brain of rats. In the present study, we investigated the effect of both the isoforms of vitamin E, alpha-tocopherol and tocotrienol against ICV STZ-induced cognitive impairment and oxidative-nitrosative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The learning and memory behavior was assessed using Morris water maze and elevated plus maze. The rats were sacrificed on day 21 and parameters of oxidative stress, nitrite levels and acetylcholinesterase activity were measured in brain homogenate. alpha-Tocopherol as well as tocotrienol treated groups showed significantly less cognitive impairment in both the behavioral paradigms but the effect was more potent with tocotrienol. Both isoforms of vitamin E effectively attenuated the reduction in glutathione and catalase and reduced the malonaldehyde, nitrite as well as cholinesterase activity in the brains of ICV STZ rats in a dose dependent manner. The study demonstrates the effectiveness of vitamin E isoforms, of which tocotrienol being more potent in preventing the cognitive deficits caused by ICV STZ in rats and suggests its potential in the treatment of neurodegenerative diseases such as Alzheimer's disease.
In an attempt to clarify the role of endogenous opioid in peripheral I2-imidazoline receptors activation for improvement of insulin action, bilateral adrenalectomy was carried out in rats with insulin resistance induced by 4-week fructose-rich chow feeding. Single intravenous (i.v.) injection of agmatine (1mg/kg) for 30 min increased the plasma beta-endorphin-like immunoreactivity (BER) in a way parallel to the reduction of plasma glucose in sham-operated fructose chow-fed rats; this action of agmatine was totally abolished by BU224 at sufficient dosage (1mg/kg, i.v.) to block I2-imidazoline receptors. The plasma glucose lowering effect of agmatine was markedly reduced but not totally deleted by adrenalectomy in fructose chow-fed rats. A direct effect of agmatine on glucose homeostasis can thus be considered. The hyperinsulinemic-euglycemic clamp technique was performed to evaluate insulin sensitivity. The effect of agmatine on elevation of the average rate of glucose infusion at the glucose clamp steady state in sham-operated fructose chow-fed rats was lessen in adrenalectomized fructose chow-fed rats, but was completely abolished by BU224. The obtained results suggest that the improvement of insulin sensitivity by agmatine is produced by two mechanisms, stimulation of adrenal gland to enhance beta-endorphin secretion and a direct activation of peripheral I2-imidazoline receptor in tissues, for the amelioration of insulin action.
Recent evidence suggests that agmatine, the metabolite of arginine by arginine decarboxylase, exists in the mammalian brain and is a novel neurotransmitter. Exogenous agmatine can modulate behaviour function, including learning and memory. The present study investigated the effects of repeated i.c.v. microinfusion of agmatine (once daily) on the reference and working memory versions of the water maze task, as well as the elevated plus maze and open field. Rats with high (100 microg), but not low (10 microg), dose of agmatine displayed reduced exploratory and locomotor activity in the open field relative to the saline controls on day 1 (received three infusions), but not day 12 (received 14 infusions). The three groups performed similarly on both days in the elevated plus maze tested prior to the open field. In the reference memory version of the water maze task, rats with agmatine treatment at both doses performed as well as the saline controls in the cued navigation (day 2), place navigation (days 3-7) and probe test (day 7). In the working memory version of the water maze task (days 8-11), the two agmatine groups generated markedly shorter path length and took significantly less time to reach the platform at the 180 s, but not 30 s, delay as compared to the saline group. These results demonstrate that repeated agmatine treatment produces transient impairments in exploratory and locomotor activity in the open field in a dose-dependent manner. Agmatine significantly facilitates spatial working memory at a longer delay, but not reference memory, suggesting its differential influence on the two types of spatial learning and memory. The underlying mechanisms need to be explored in the future.
The objective of the present study was to investigate the effect of the administration of resveratrol (RV) on memory and on acetylcholinesterase (AChE) activity in the cerebral cortex, hippocampus, striatum, hypothalamus, cerebellum and blood in streptozotocin-induced diabetic rats. The animals were divided into six groups (n=6-13): Control/saline; Control/RV 10 mg/kg; Control/RV 20 mg/kg; Diabetic/saline; Diabetic/RV 10 mg/kg; Diabetic/RV 20 mg/kg. One day after 30 days of treatment with resveratrol the animals were submitted to behavioral tests and then submitted to euthanasia and the brain structures and blood were collected. The results showed a decrease in step-down latency in diabetic/saline group. Resveratrol (10 and 20 mg/kg) prevented the impairment of memory induced by diabetes. In the open field test, no significant differences were observed between the groups. In relation to AChE activity, a significant increase in diabetic/saline group (P<0.05) was observed in all brain structures compared to control/saline group. However, AChE activity decreased significantly in control/RV10 and control/RV20 (P<0.05) groups in cerebral cortex, hippocampus and striatum, while no significant differences were observed in diabetic/RV10 and diabetic/RV20 groups in all brain structures compared to control/saline group. Blood AChE activity increased significantly in diabetic/saline group (P<0.05) decreased in control/RV10, control/RV20 and diabetic/RV20 groups (P<0.05) compared to control/saline group. In conclusion, the present findings showed that treatment with resveratrol prevents the increase in AChE activity and consequently memory impairment in diabetic rats, demonstrating that this compound can modulate cholinergic neurotransmission and consequently improve cognition.
The reaction of lipid peroxides in animal tissues with thiobarbituric acid was dependent on pH of the reaction mixture as was the case for linoleic acid hydroperoxide. The optimum pH was found to be 3.5. Taking this fact into consideration, a standard procedure for the assay of lipid peroxide level in animal tissues by their reaction with thiobarbituric acid was developed as follows. Ten percent ( tissue homogenate was mixed with sodium dodecyl sulfate, acetate buffer (pH 3.5), and aqueous solution of thiobarbituric acid. After heating at 95°C for 60 min, the red pigment produced was extracted with n-butanol-pyridine mixture and estimated by the absorbance at 532nm. As an external standard, tetramethoxy-propane was used, and lipid peroxide level was expressed in terms of nmol malondialdehyde. Using this method, the liped peroxide level in the liver of rats suffering from carbon tetrachloride intoxication was investigated. The results were in good agreement with previously reported data obtained by measuring diene content.
The concept that memory loss in ageing might be attributable to deficiencies in cholinergic function was first proposed two decades ago. This proposal gained additional definition when pathology was found in the basal forebrain cholinergic system of patients with Alzheimer's disease, and substantial deterioration of these neurons was detected in several animal models of ageing. A recently developed method for selectively removing basal forebrain cholinergic neurons using an immunotoxin provides a powerful tool for examining the function of the basal forebrain cholinergic system. This review will address new information that has come from this approach, with an emphasis on understanding the contribution of basal forebrain cholinergic neurons to age-related cognitive impairment.
Diabetes mellitus is a risk factor for ischemic, but not hemorrhagic stroke. The frequency of transient ischemic attacks is not increased in patients with diabetes compared to the general population. Diabetes mellitus is associated with higher mortality, worse functional outcome, more severe disability after stroke and a higher frequency of recurrent stroke. Diabetes is not associated with an increased size of cerebral infarction. Controversy exists regarding whether hyperglycemia adversely affects stroke outcome or primarily reflects stroke severity. Cerebral blood flow disturbances, impaired cerebrovascular reactivity, and damage to large and small extra- and intracranial cerebral vessels have been found in humans and animals with diabetes. Combinations of some or all of these factors may underlie the high incidence and worse outcome of stroke in patients with diabetes. Knowledge of these pathophysiologic factors will assist in the design of future intervention strategies.
The hypothesis is forwarded that sporadic late-onset Alzheimer disease is caused by non-insulin dependent diabetes mellitus which is confined to the brain. This hypothesis is based on the findings of Frölich and coworkers (this volume) who clearly demonstrate a perturbation of the neuronal insulin/ insulin receptor signal transduction pathway which is considered to be the pathobiochemical basis for the drastic reduction in glucose/energy metabolism in Alzheimer brain. As a consequence of this abnormality, advanced glycation end products are formed. Münch et al. (this volume) evaluate the impacts of the latter related to oxidative stress and the formation of beta-amyloid and neurofibrillary tangles.
Neural tissue is entirely dependent on glucose for normal metabolic activity. Since glucose stores in the brain and retina are negligible compared to glucose demand, metabolism in these tissues is dependent upon adequate glucose delivery from the systemic circulation. In the brain, the critical interface for glucose transport is at the brain capillary endothelial cells which comprise the blood-brain barrier (BBB). In the retina, transport occurs across the retinal capillary endothelial cells of the inner blood-retinal barrier (BRB) and the retinal pigment epithelium of the outer BRB. Because glucose transport across these barriers is mediated exclusively by the sodium-independent glucose transporter GLUT1, changes in endothelial glucose transport and GLUT1 abundance in the barriers of the brain and retina may have profound consequences on glucose delivery to these tissues and major implications in the development of two major diabetic complications, namely insulin-induced hypoglycemia and diabetic retinopathy. This review discusses the regulation of brain and retinal glucose transport and glucose transporter expression and considers the role of changes in glucose transporter expression in the development of two of the most devastating complications of long-standing diabetes mellitus and its management.
Recent evidence suggests that agmatine, which is an intermediate in polyamine biosynthesis, might be an important neurotransmitter in mammals. Agmatine is synthesized in the brain, stored in synaptic vesicles in regionally selective neurons, accumulated by uptake, released by depolarization, and inactivated by agmatinase. Agmatine binds to alpha2-adrenoceptors and imidazoline binding sites, and blocks NMDA receptor channels and other ligand-gated cationic channels. Furthermore, agmatine inhibits nitric oxide synthase, and induces the release of some peptide hormones. As a result of its ability to inhibit both hyperalgesia and tolerance to, and withdrawal from, morphine, and its neuroprotective activity, agmatine has potential as a treatment of chronic pain, addictive states and brain injury.
The effect of streptozotocin-induced diabetes on cholinesterases activities was studied in the retina and, for comparison, in other nervous and nonnervous tissues. Streptozotocin diabetes did not affect acetylcholinesterase activity in the retina but increased its activity in the cerebral cortex (100%) and in serum (55%), and decreased it by 30-40% in erythrocytes. The butyrylcholinesterase activity was decreased by 30-50% in retina and hippocampus and to a lesser extent in retinal pigment epithelium from rats treated with streptozotocin for one week. Changes observed in cholinesterase activities were not correlated with the fasting blood glucose concentration. The results suggest that diabetes might influence a specific subset of cells and isoforms of cholinesterases. This, in turn, could lead to alterations associated with diabetes complications.
It is established that agmatine, an endogenously formed decarboxylated arginine, is a weak competitive inhibitor of neuronal nitric-oxide synthase (nNOS) with an apparent Ki value of 660 microM [Biochem J 316:247-249, 1996]. Although agmatine is known to bind to alpha-adrenergic and imidazoline receptors, it has been suggested that some of the pharmacological actions of agmatine, such as the prevention of morphine tolerance, may be due to the inhibition of nNOS. In the current study, we have discovered that agmatine, at concentrations much lower than the reported Ki value, leads to a time-, concentration-, NADPH-, and calmodulin-dependent irreversible inactivation of nNOS. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (Ki) and a pseudo first-order inactivation constant (k(inact)) of 29 microM and 0.01 min(-1), respectively. As determined by high-performance liquid chromatography analysis, the mechanism of inactivation involves alteration of the prosthetic heme moiety of nNOS, in part to protein-bound products. Moreover, we discovered that agmatine causes a 3-fold increase in the NADPH oxidase activity of nNOS leading to the production of H2O2 and is a likely cause for the inactivation of the enzyme. Both the inactivation of nNOS and the oxidative stress produced should now be considered in the pharmacological actions of agmatine as well as provide insight into the potential biological effects of endogenously formed agmatine.
To perform serial neuropsychological assessments to detect vascular risk factors for cognitive decline in the Atherosclerosis Risk in Communities cohort, a large biracial, multisite, longitudinal investigation of initially middle-aged individuals.
The authors administered cognitive assessments to 10,963 individuals (8,729 white individuals and 2,234 black individuals) on two occasions separated by 6 years. Subjects ranged in age at the first assessment from 47 to 70 years. The cognitive assessments included the delayed word recall (DWR) test, a 10-word delayed free recall task in which the learning phase included sentence generation with the study words, the digit symbol subtest (DSS) of the Wechsler Adult Intelligence Scale-Revised and the first-letter word fluency (WF) test using letters F, A, and S.
In multivariate analyses (controlling for demographic factors), the presence of diabetes at baseline was associated with greater decline in scores on both the DSS and WF (p < 0.05), and the presence of hypertension at baseline was associated with greater decline on the DSS alone (p < 0.05). The association of diabetes with cognitive decline persisted when analysis was restricted to the 47- to 57-year-old subgroup. Smoking status, carotid intima-media wall thickness, and hyperlipidemia at baseline were not associated with change in cognitive test scores.
Hypertension and diabetes mellitus were positively associated with cognitive decline over 6 years in this late middle-aged population. Interventions aimed at hypertension or diabetes that begin before age 60 might lessen the burden of cognitive impairment in later life.
This review summarises the results and discussions of an UNESCO-MCBN supported symposium on oxidative stress and its role in the onset and progression of diabetes. There is convincing experimental and clinical evidence that the generation of reactive oxygen species (ROI) is increased in both types of diabetes and that the onset of diabetes is closely associated with oxidative stress. Nevertheless there is controversy about which markers of oxidative stress are most reliable and suitable for clinical practice. There are various mechanisms that contribute to the formation of ROI. It is generally accepted that vascular cells and especially the endothelium become one major source of ROI. An important role of oxidative stress for the development of vascular and neurological complications is suggested by experimental and clinical studies. The precise mechanisms by which oxidative stress may accelerate the development of complications in diabetes are only partly known. There is however evidence for a role of protein kinase C, advanced glycation end products (AGE) and activation of transcription factors such as NF kappa B, but the exact signalling pathways and the interactions with ROI remain a matter of discussion. Additionally, results of very recent studies suggest a role for ROI in the development of insulin resistance. ROI interfere with insulin signalling at various levels and are able to inhibit the translocation of GLUT4 in the plasma membrane. Evidence for a protective effect of antioxidants has been presented in experimental studies, but conclusive evidence from patient studies is missing. Large-scale clinical trials such as the DCCT Study or the UKPDS Study are needed to evaluate the long-term effects of antioxidants in diabetic patients and their potential to reduce the medical and socio-economic burden of diabetes and its complications.