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Quercetin promotes behavioral recovery and biomolecular changes of melanocortin-4 receptor in mice with ischemic stroke
Abstract
Objectives:
Ischemic stroke is known as a common causes of disability, lower psychological well-being as well as preventable death. The pathogenesis of ischemic stroke process becomes worse immediately after oxidative stress occurs. One of the flavonoids with antioxidant abilities is quercetin. This study was aimed to investigate quercetin administration on the behavioral functions (motor and sensory) and expression of melanocortin-4 receptor (MC4R) in mice with ischemic stroke.
Methods:
Male ICR mice were divided into sham, stroke, stroke with quercetin 100, 150, and 200 mg/kg. The stroke model was performed by blocking the left common carotid artery for 2 h. Quercetin was intraperitoneally administered daily for seven days. Evaluation was conducted during two weeks after induction using ladder rung walking test and narrow beam test for motoric function and adhesive removal tape test for sensory function. On day-14 mice were sacrificed, MC4R expression in the dorsal striatum was determined using RT-PCR.
Results:
Stroke decreased the motor, sensory function and MC4R mRNA expression in dorsal striatum. Quercetin improved motor and sensory function, and upregulated expression of MC4R.
Conclusions:
Quercetin administration after ischemic stroke improves behavioral function, possibly through the upregulation of MC4R in the brain.
... Compared to free quercetin or quercetin-carrying exosome (quercetin-EXO) therapy, treatment with quercetin/mAb gAP43-EXO dramatically reduced infarct size and improved neurological recovery in MCAO reperfusion-induced rats (Guo et al., 2021) (Figure 3). Simultaneously, quercetin improved the IS-associated motor and sensory deficits in the dorsal striatum, which may be related to the upregulation of MC4R-mRNA expression (Ulya et al., 2021). More intuitively, quercetin showed 6.79 2 ± 0.41 right turn in rats in the permanent MCAO model and 9.31 ± 0.33 right turn in the control group. ...
Ischemic stroke (IS) is characterized by high recurrence and disability; however, its therapies are very limited. As one of the effective methods of treating acute attacks of IS, intravenous thrombolysis has a clear time window. Quercetin, a flavonoid widely found in vegetables and fruits, inhibits immune cells from secreting inflammatory cytokines, thereby reducing platelet aggregation and limiting inflammatory thrombosis. In pre-clinical studies, it has been shown to exhibit neuroprotective effects in patients with ischemic brain injury. However, its specific mechanism of action remains unknown. Therefore, this review aims to use published data to elucidate the potential value of quercetin in patients with ischemic brain injury. This article also reviews the plant sources, pharmacological effects, and metabolic processes of quercetin in vivo , thus focusing on its mechanism in inhibiting immune cell activation and inflammatory thrombosis as well as promoting neuroprotection against ischemic brain injury.
Objectives
Brain injury resulting from an ischemic stroke affects cognitive performance by disrupting the hippocampus. Several processes are involved in brain injury progression, including inflammation, glutamate excitotoxicity, and modulated brain peptide systems such as the melanocortin system. Reports show that quercetin exerts neuroprotective activity. This study investigates quercetin’s role in the cognitive function of ischemic stroke-induced mice and the possible mechanisms involved.
Materials and Methods
ICR mice were used. The left unilateral common carotid artery occlusion was conducted for 4 h to induce an ischemic stroke in the mice. Quercetin 50, 100, and 200 mg/kg were administered to separate groups intraperitoneally for 7 days. Cognitive function was examined using the T-maze test. The hippocampal mRNA expressions of NR2A, NR2B, melanocortin 4 receptor (MC4R), pro-opiomelanocortin precursors (POMC), and nuclear factor 2 (Nrf2) were examined using reverse transcription-polymerase chain reaction.
Results
It was found that stroke disrupted cognitive function. Quercetin administration ameliorated cognitive impairment. Quercetin attenuated the stroke-induced decrease in MC4R mRNA expression. Moreover, quercetin suppressed the stroke-induced increase in the hippocampal mRNA expression of NR2A.
Conclusion
Quercetin ameliorates cognitive deficits and normalizes impaired hippocampal melanocortin and glutamatergic signaling in ischemic stroke-induced mice.
Background
The purpose of this study was to investigate the molecular mechanisms and material basis of Huangqi Guizhi Wuwu Decoction (HGWD) in treating clinical Ischemic stroke (IS) using network pharmacology and molecular docking techniques.
Materials and Methods
The study retrieved and screened the practical components of HGWD from the TCMSP, BATMAN-TCM, and ETCM databases. Target prediction was performed using the SwissTargetPrediction database, and disease targets for IS were obtained from the Gene Cards, DisGeNET, and OMIM databases. The regulatory targets for HGWD in treating IS were obtained by VENN analysis, and the protein-protein interaction network of disease targets was constructed using the STRING database. GO analysis and KEGG enrichment analysis were performed using the DAVID database.
Results
A total of 227 active ingredients and 354 drug targets were obtained for HGWD, and after combining them with 4,402 disease targets, 253 potential targets for HGWD to treat IS were identified. GO and KEGG enrichment analyses yielded 251 gene functions and 422 pathways. The study found that the active components in HGWD may treat IS through the IL-17 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, and other targets.
Conclusion
The study identified potential molecular mechanisms and the material basis of HGWD in treating clinical IS. The results suggest that HGWD could be a promising therapeutic approach for treating IS, and further experimental validation is needed.
Stroke and acute myocardial infarction are leading causes of mortality worldwide. The latter accounts for approximately 9 million deaths annually. In turn, ischemic stroke is a significant contributor to adult physical disability globally. While reperfusion is crucial for tissue recovery, it can paradoxically exacerbate damage through oxidative stress (OS), inflammation, and cell death. Therefore, it is imperative to explore diverse approaches aimed at minimizing ischemia/reperfusion injury to enhance clinical outcomes. OS primarily arises from an excessive generation of reactive oxygen species (ROS) and/or decreased endogenous antioxidant potential. Natural antioxidant compounds can counteract the injury mechanisms linked to ROS. While promising preclinical results, based on monotherapies, account for protective effects against tissue injury by ROS, translating these models into human applications has yielded controversial evidence. However, since the wide spectrum of antioxidants having diverse chemical characteristics offers varied biological actions on cell signaling pathways, multitherapy has emerged as a valuable therapeutic resource. Moreover, the combination of antioxidants in multitherapy holds significant potential for synergistic effects. This study was designed with the aim of providing an updated overview of natural antioxidants suitable for preventing myocardial and cerebral ischemia/reperfusion injuries.
Stroke is one of the major causes of death and severe disability worldwide. At present, intravenous thrombolysis to restore blood flow at the ischemic part of the brain is the main treatment for ischemic stroke. However, even if patients are treated in time during the therapeutic window of thrombolytic drugs, thrombolysis causes a sharp increase in oxygen concentration at the injury site after ischemia–reperfusion, leading to the outbreak of free radicals, which further aggravates the brain injury. Neuroprotective therapy, which is combined with thrombolytic therapy, is an important treatment for ischemic stroke and metabolic disorders caused by ischemic brain injury. It can inhibit various types of cell necrosis, increase cell viability, delay neuronal death, and promote the recovery of neural functions. This review summarizes novel neuroprotective treatments for stroke, especially nanotechnology‐assisted advanced targeted therapies. Future prospects and challenges are also discussed for the development of neuroprotective nanomaterials.
Ischemic stroke (IS) is a leading cause of death and disability worldwide. Currently, the main therapeutic strategy involves the use of intravenous thrombolysis to restore cerebral blood flow to prevent the transition of the penumbra to the infarct core. However, due to various limitations and complications, including the narrow time window in which this approach is effective, less than 10% of patients benefit from such therapy. Thus, there is an urgent need for alternative therapeutic strategies, with neuroprotection against the ischemic cascade response after IS being one of the most promising options. In the past few decades, polyphenolic compounds have shown great potential in animal models of IS because of their high biocompatibility and ability to target multiple ischemic cascade signaling pathways, although low bioavailability is an issue that limits the applications of several polyphenols. Here, we review the pathophysiological changes following cerebral ischemia and summarize the research progress regarding the applications of polyphenolic compounds in the treatment of IS over the past 5 years. Furthermore, we discuss several potential strategies for improving the bioavailability of polyphenolic compounds as well as some essential issues that remain to be addressed for the translation of the related therapies to the clinic.
Excessive alcohol intake affects hippocampal function and neuronal communication through oxidative stress and mitochondrial impairment. Previous studies have suggested that the melanocortin system (MCS) plays an essential role in alcohol consumption and addiction. The MCS is a hypothalamic region involved in regulating inflammatory processes in the brain, and its pharmacological activation through the melanocortin-4 receptor (MC4R) reduces both alcohol consumption and the neuroinflammatory responses in the brain. However, the cellular mechanisms involved in the beneficial actions of MCS against ethanol toxicity are not entirely understood. The objective of this study was to investigate the protective role of the MC4R pharmacological activator RO27-3225 on oxidative damage and mitochondrial impairment present in hippocampal neuronal cultures acutely exposed to ethanol (50, 75 mM, 24 h). Pre-treatment with RO27-3225 (250 nM, 1 h) prevented reactive oxygen species (ROS) increase, dysregulation of cytosolic calcium homeostasis, and mitochondrial potential loss induced by ethanol. Improvement of mitochondrial failure produced by RO27-3225 was accompanied by a significant increase in ATP production in ethanol-treated neurons. More importantly, RO27-3225 promoted the activation of the antioxidant pathway Nrf-2, demonstrated by an increase in the expression and nuclear translocation of Nrf-2, and upregulation of mRNA levels of NAD(P)H quinone oxidoreductase 1 (NQO1), an antioxidant enzyme which expression is activated by this pathway. These results suggest that the stimulation of MC4R prevents oxidative damage and mitochondrial stress induced by ethanol through the activation of the Nrf-2 pathway in cultured hippocampal neurons. These results are novel and demonstrate the critical function of MC4R in promoting antioxidant defense and reducing mitochondrial damage produced by ethanol in the brain.
The aim of this study was to examine the physical characteristics, solubility, and in vitro dissolution profile of quercetin-PEG 8000 solid dispersion prepared by melting method. Solid dispersion was prepared by melting method with various ratios of quercetin and PEG 8000 (1:1; 1:2; 1:3). The solid dispersion was characterized using differential thermal analyzer (DTA), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), and fourier transform infrared spectroscopy (FTIR). The solubility and in vitro dissolution of quercetin-PEG 8000 solid dispersion were evaluated and compared to physical mixture and pure quercetin. The solid dispersion of quercetin-PEG 8000 has lower melting point and crystal peak intensity compared to pure quercetin and physical mixture. The infrared spectra of solid dispersions and physical mixtures indicated the occurrence of physical interactions that involved weak bonding forces such as the hydrogen bond between quercetin functional groups and O-H group. The solubility and the dissolution rate enhanced in accordance with increasing of PEG 8000 amount.
Previous studies have demonstrated that traumatic brain injury (TBI) may cause neurological deficits and neuronal cell apoptosis. Quercetin, one of the most widely distributed flavonoids, possesses anti‑inflammatory, anti‑blood coagulation, anti‑ischemic and anti‑cancer activities, and neuroprotective effects in the context of brain injury. The purpose of the present study was to investigate the neuroprotective effects of quercetin in TBI. A total of 75 rats were randomly arranged into 3 groups as follows: Sham group (Sham); TBI group (TBI); and TBI + quercetin group (Que). Brain edema was evaluated by analysis of brain water content. The neurobehavioral status of the rats was evaluated by Neurological Severity Scoring. Immunohistochemical and western blot analyses were used to measure the expression of certain proteins. The results of the present study demonstrated that post‑TBI administration of quercetin may attenuate brain edema, in addition to improving motor function in rats. Additionally, quercetin caused a marked inhibition of extracellular signal‑regulated kinase 1/2 phosphorylation and activated Akt serine/threonine protein kinase phosphorylation, which may result in attenuation of neuronal apoptosis. The present study provided novel insights into the mechanism through which quercetin may exert its neuroprotective activity in a rat model of TBI.
Objectives
Gait recovery is an important goal in stroke patients. Several studies have sought to uncover relationships between specific brain lesions and the recovery of gait, but the effects of specific brain lesions on gait remain unclear. Thus, we investigated the effects of stroke lesions on gait recovery in stroke patients.
Materials and Methods
In total, 30 subjects with stroke were assessed in a retrograde longitudinal observational study. To assess gait function, the functional ambulation category (FAC) was tested four times: initially (within 2 weeks) and 1, 3, and 6 months after the onset of the stroke. Brain lesions were analyzed via overlap, subtraction, and voxel‐based lesion symptom mapping (VLSM).
Results
Ambulation with FAC improved significantly with time. Subtraction analysis showed that involvement of the corona radiata, internal capsule, globus pallidus, and putamen were associated with poor recovery of gait throughout 6 months after onset. The caudate nucleus did influence poor recovery of gait at 6 months after onset. VLSM revealed that corona radiata, internal capsule, globus pallidus, putamen and cingulum were related with poor recovery of gait at 3 months after onset. Corona radiata, internal capsule, globus pallidus, putamen, primary motor cortex, and caudate nucleus were related with poor recovery of gait at 6 months after onset.
Conclusion
Results identified several important brain lesions for gait recovery in patients with stroke. These results may be useful for planning rehabilitation strategies for gait and understanding the prognosis of gait in stroke patients.
Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions.
Increasing interest has recently focused on determining whether several natural compounds, collectively referred to as nutraceuticals, may exert neuroprotective actions in the developing, adult, and aging nervous system. Quercetin, a polyphenol widely present in nature, has received the most attention in this regard. Several studies
in vitro
, in experimental animals and in humans, have provided supportive evidence for neuroprotective effects of quercetin, either against neurotoxic chemicals or in various models of neuronal injury and neurodegenerative diseases. The exact mechanisms of such protective effects remain elusive, though many hypotheses have been formulated. In addition to a possible direct antioxidant effect, quercetin may also act by stimulating cellular defenses against oxidative stress. Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2). In addition, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection.
Flavonoids belong to a category of polyphenolic compounds that are produced exclusively in plants. These compounds are able to bring about various biological and pharmacological activities in animal cells. It is generally believed that most mammals need to consume polyphenols from plants due to their antioxidant properties in order to stay healthy. The antioxidants are essential for protecting the cells from undergoing chemical damage due to oxidation. Many compounds are known to have both antioxidant and pro-oxidant properties. The pro-oxidant properties can either be favourable or detrimental to biological systems and can affect the progress of chronic diseases in human beings. Quercetin, the most plentiful flavonoid, acts as both an antioxidant and a pro-oxidant. Currently, there is no reliable method for maintaining a balance between these two activities in the whole organism. Therefore, this review focuses onMetabolism, bioactivity and both the antioxidant and pro-oxidant effects of flavonoids.
The role of the melanocortin (MC) system in feeding behavior is well established. Food intake is potently suppressed by central infusion of the MC 3/4 receptor agonist α-melanocyte stimulating hormone (α-MSH), whereas the MC 3/4 receptor inverse-agonist Agouti Related Peptide (AGRP) has the opposite effect. MC receptors are widely expressed in both hypothalamic and extra-hypothalamic brain regions, including nuclei involved in food reward and motivation, such as the nucleus accumbens (NAc) and the ventral tegmental area. This suggests that MCs modulate motivational aspects of food intake. To test this hypothesis, rats were injected intracerebroventricularly with α-MSH or AGRP and their motivation for sucrose was tested under a progressive ratio schedule of reinforcement. Food motivated behavior was dose-dependently decreased by α-MSH. Conversely, AGRP increased responding for sucrose, an effect that was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast to progressive ratio responding, free intake of sucrose remained unaltered upon α-MSH or AGRP infusion. In addition, we investigated whether the effects of α-MSH and AGRP on food motivation were mediated by the NAc shell. In situ hybridization of MC3 and MC4 receptor expression confirmed that the MC4 receptor was expressed throughout the NAc, and injection of α-MSH and AGRP into the NAc shell caused a decrease and an increase in motivation for sucrose, respectively. These data show that the motivation for palatable food is modulated by MC4 receptors in the NAc shell, and demonstrate cross-talk between the MC and dopamine system in the modulation of food motivation.
Indirect evidence indicates that, in cerebral ischemia, melanocortins have neuroprotective effects likely mediated by MC₄ receptors. To gain direct insight into the role of melanocortin MC₄ receptors in ischemic stroke, we investigated the effects of a highly selective MC₄ receptor agonist. Gerbils were subjected to transient global cerebral ischemia by occluding both common carotid arteries for 10 min. In saline-treated stroke animals, an impairment in learning and memory occurred that, at day 11 after stroke, was associated with hippocampus up-regulation of tumor necrosis factor-α (TNF-α), BAX, activated extracellular signal-regulated kinases (ERK1/2), c-jun N-terminal kinases (JNK1/2) and caspase-3, down-regulation of Bcl-2, and neuronal loss. Treatment for 11days with the selective melanocortin MC₄ receptor agonist RO27-3225, as well as with the well known non-selective [Nle⁴,D-Phe⁷]α-melanocyte-stimulating hormone (NDP-α-MSH) as a reference non-selective melanocortin, counteracted the inflammatory and apoptotic responses, as indicated by the changes in TNF-α, BAX, ERK1/2, JNK1/2, caspase-3 and Bcl-2 protein expression. Furthermore, melanocortin treatment reduced neuronal loss and dose-dependently improved learning and memory. These positive effects were associated with overexpression of Zif268, an immediate early gene involved in injury repair, synaptic plasticity and memory formation. Pharmacological blockade of MC₄ receptors with the selective MC₄ receptor antagonist HS024 prevented all effects of RO27-3225 and NDP-α-MSH. These data give direct evidence that stimulation of MC₄ receptors affords neuroprotection and promotes functional recovery from stroke, by counteracting prolonged and/or recurrent inflammatory and apoptotic responses, and likely by triggering brain repair pathways.
Research on cancer and other conditions has shown flavonoids and sphingolipids to be food components capable of exerting chemoprotective action. Nevertheless, little is known about their effects on healthy individuals and their potential usefulness as therapeutic agents. The present study examined the possible action of a dietary flavonoid, quercetin, and a sphingolipid, sphingomyelin, as functional foods in healthy animals. In particular, the effect on animal growth of supplementing a conventional diet with one or other of these substances (0.5 % quercetin and 0.05 % sphingomyelin) was considered. Possible action affecting intestinal physiology was also analysed by measuring the uptake of sugar and dipeptide, mediated by the Na(+)-dependent sugar transporter SGLT1 and the dipeptide Na(+)/H(+) exchanger PEPT1 respectively, and the activity of related intestinal enzymes such as sucrase, maltase and aminopeptidase N. Both substances seemed to modify small intestinal activity in healthy mice, altering intestinal enzymatic activity and nutrient uptake. These effects observed in the small intestine did not impair normal development of the animals, as no differences in serum biochemical parameters or in organ and body weights were found. The findings should help in elucidating the mechanisms of action of these food components with a view to their possible use in the prevention of certain pathological conditions.
The modifying effects of Crocus sativus (CS) stigma extract on neurobehavioral activities, malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase (SOD), catalase (CAT), and Na(+),K(+)-ATPase activities, and glutamate (Glu) and aspartate (Asp) content were examined in the middle cerebral artery (MCA) occlusion (MCAO) model of acute cerebral ischemia in rats. The right MCA of male Wistar rats was occluded for 2 hours using intraluminal 4-0 monofilament, and reperfusion was allowed for 22 hours. MCAO caused significant depletion in the contents of GSH and its dependent enzymes while significant elevation of MDA, Glu, and Asp. The activities of Na(+),K(+)-ATPase, SOD, and CAT were decreased significantly by MCAO. The neurobehavioral activities (grip strength, spontaneous motor activity, and motor coordination) were also decreased significantly in the MCAO group. All the alterations induced by ischemia were significantly attenuated by pretreatment of CS (100 mg/kg of body weight, p.o.) 7 days before the induction of MCAO and correlated well with histopathology by decreasing the neuronal cell death following MCAO and reperfusion. The present results may suggest the effectiveness of CS in focal ischemia most probably by virtue of its antioxidant property.
The assessment of both histological and functional long-term outcomes after cerebral ischemia is increasingly recommended for preclinical studies. Whereas correlations between behavioral impairments and primary ischemic lesion are documented, little is known about their relationships with remote nonischemic regions that undergo secondary degeneration, such as the thalamus. Anesthetized rats were subjected to mild (30 min) or severe (60 min) occlusion of the middle cerebral artery. Two months after ischemia, sensorimotor behavior was assessed according to the neurological score, limb-placing, adhesive-removal, and staircase tests; the final histological lesion was measured after this assessment. Cortical damage was correlated to all transient and long-lasting sensorimotor deficits, whereas striatal lesion was more consistently reflected by the forelimb-placing reflexes and adhesive-removal motor deficits. By contrast, the thalamic atrophy was not correlated to early neurological impairment, but rather to the late sensory deficit at the adhesive-removal test and to the skilled forepaw reaching alteration at the staircase test. This suggests that thalamus contributes, albeit moderately, to the ischemia-induced long-lasting sensorimotor deficits, some of which represent relevant targets for therapeutic interventions.
Background
Oxidative stress plays a pivotal role in the pathophysiology and pathogenesis of mental diseases, such as depression or anxiety. Psychological stress induced by predatory stimulus is one of the models that explain how induced affective behavior is manifested as a depression-like state. Quercetin is a flavonoid that exhibits potential pharmacological activity on mental diseases. Thus, the present study was designed to investigate the effect of quercetin on innate fear and affective behavior induced by repeated predator stress exposure on mice.
Materials and methods
ICR mice were exposed to predatory stress for 3 days. Quercetin at a dose of 50 mg/kg was given intraperitoneally along with stress induction. The freezing behavior during the stress induction was analyzed. The anxiety-like and depressive-like behaviors and cognitive and motor functions were examined on the last day of induction.
Results
Predatory stress increased the affective behaviors (anxiety-like and depressive-like behaviors) and produced freezing behavior without alterations in the cognitive function and exploratory behavior. Treatment with quercetin 50 mg/kg attenuated the freezing, anxiety-like and depressive-like behaviors.
Conclusions
Repeated predator stress exposure causes both innate fear and depression-like state for the prey animals. Quercetin may have a protective effect against depression and alleviates the fear of traumatic events.
Ischemic stroke is insufficient or interrupted of blood flow to an area of the brain, typically caused by blockage of an artery and can result in brain damaged. This study was aimed to investigate the efficacy of Recombinant Human Erythropoietin (rHuEPO) as a neuroprotection (antiapoptotic agent) on rat with ischemic stroke induced by right common carotid artery occlusion. Animals were divided into five groups included sham group, ischemic stroke group and treatment group of rHuEPO. rHuEPO was administered intravenously once a day for 7 days at dose 1000, 5000, 10000 IU/Kg a week after induced by right common carotid artery occlusion surgery. The repair of brain damage was evaluated by Y maze for cognitive repair, ladder rung walking and forelimb asymmetry test for motor repair, measured on day 0, 1, 3 and 7. The result showed that treatment with rHuEPO significantly enhanced spatial memory at 5000 and 10000 IU/Kg in day 7 compare to ischemic group (p = 0.0260, p = 0.0286 respectively) and improved motoric function in day 7 compare to ischemic group (p = 0.0064, p = 0.0102 respectively). rHuEPO significantly reduce area infarct at 1000 IU 5000 IU and 10000 IU/Kg compare to ischemic group (p = 0.0265, p = 0.0016 p = 0.0024 respectively). Furthermore, there were significant differences on caspase 3 expression in each group. © 2019, Indian Journal of Public Health Research and Development. All rights reseved.
Background: Quercetin (QUR), as an antioxidant flavonoid, exhibits potential role in the amelioration of cerebral ischaemia; however, poor solubility as well as oral absorption results low serum and tissue levels for this drug.
Purpose of the study: To enhance bioavailability, this study aims to prepare QUR nanoemulsions and administer via non-invasive nasal route in order to evaluate the drug targeting in brain.
Methods: Quercetin mucoadhesive nanoemulsion (QMNE) was prepared (ionic gelation method) and optimized using various parameters, that is, particle size, entrapment efficiency, zeta potential and ex vivo permeation study.
Results: The results observed for optimized QMNE were as follows: mean globule size (91.63 ± 4.36 nm), zeta potential (−17.26 ± 1.04 mV), drug content (99.84 ± 0.34%) and viscosity (121 ± 13 cp). To evaluate the extent of bioavailability for QMNE via post-intranasal (i.n.) administration, Ultra performance liquid chromatography-mass spectroscopy (UPLC-ESI-Q-TOF-MS/MS)-based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency (9333.33 ± 39.39%) and brain drug-targeting potential (2181.83 ± 5.69%) which revealed enhanced QUR brain bioavailability as compared to intravenous administration (i.v.). Furthermore, improved neurobehavioral activity (locomotor and grip strength), histopathology and reduced infarction volume effects were observed in middle cerebral artery occlusion (MCAO)–induced cerebral ischemic rats model after i.n. administration of QMNE.
Conclusion: This study supports a significant role for QMNE in terms of high brain-targeting potential and formulation efficiency due to ease of access and effective targeting in brain.
Injuries and diseases that occur in the nervous system are common and have few effective treatments. Previous studies have shown that quercetin has a therapeutic effect on nervous system injuries, but its potential effects on and mechanisms of action related to behavioral recovery and axonal regrowth have not been investigated. Here, we showed that quercetin administration promotes behavioral recovery following sciatic nerve-crush injury in mice. Long-term evaluation showed that mice administered 20 mg/Kg/d quercetin for 35 days had a greater sensorimotor recovery compared with all other treatment groups. The mechanisms behind these effects were further investigated, and quercetin was found to regulate the expression of genes involved in regeneration and trophic support. Moreover, quercetin increased cAMP expression and downstream pathway activation, which directly leads to neuronal growth activation in peripheral axon regeneration. Additionally, quercetin enhanced axon remyelination, motor nerve conduction velocity (MNCV), and plantar muscle function, indicating that the degree of distal portion hypotrophy during the peripheral axon regeneration process was reduced. These results suggest that quercetin accelerates functional recovery by upregulating neuronal intrinsic growth capacity and postponing distal atrophy. Overall, quercetin triggered multiple effects to promote behavioral recovery following sciatic nerve-crush injury in mice.
Freezing of gait (FOG) is a common and debilitating, but largely mysterious, symptom of Parkinson's disease. In this review, we will discuss the cerebral substrate of FOG focusing on brain physiology and animal models. Walking is a combination of automatic movement processes, afferent information processing and intentional adjustments. Thus, normal gait requires a delicate balance between various interacting neuronal systems. To further understand gait control and specifically FOG, we will discuss the basic physiology of gait, animal models of gait disturbance including FOG, alternative etiologies of FOG and functional magnetic resonance studies investigating FOG. The outcome of these studies point to a dynamic network of cortical areas such as the supplementary motor area, as well as subcortical areas such as the striatum and the mesencephalic locomotor region (MLR) including the pedunculopontine nucleus (PPN). Additionally, we will review PPN (area) stimulation as a possible treatment for FOG, and ponder whether PPN stimulation truly is the right step forward. This article is protected by copyright. All rights reserved.
Cerebral ischemia/reperfusion (I/R) is a major cause of severe disability and death all worldwide. However, therapeutic options to minimize the detrimental effects of cerebral I/R injury are limited. Recent research has demonstrated that quercetin mediates neuroprotective effects associated with the activation of the Akt signaling pathway in the cerebral I/R brain. Therefore, the aim of this study was to further investigate the mechanisms of cognitive deficits induced by cerebral I/R injury and the effects of quercetin on these mechanisms. First, we assessed anxiety-like behavioral and cognitive impairment using the open field test and the Morris water maze test, respectively. Next, we examined the severity of apoptosis by staining hippocampal neurons by the Cresyl violet method. Third, we used western blot analysis to investigate the expression of total and phosphorylated Akt, ASK1, JNK3, c-Jun and caspase-3 after I/R injury. Our results revealed that mice subjected to bilateral common carotid occlusion exhibited severe anxiety-like behavior, learning and memory impairment, cell damage and apoptosis. These severe effects were attenuated by administration of quercetin. Further, western blot analysis revealed that quercetin increased p-Akt expression and decreased p-ASK1, p-JNK3 and cleaved caspase-3 expression after cerebral I/R injury and led to inhibition of neuronal apoptosis. Conversely, treatment with LY294002 (a selective inhibitor of Akt1) reversed the effects of quercetin. In conclusion, these findings highlight the important role of quercetin in protecting against cognitive deficits and inhibiting neuronal apoptosis via the Akt signaling pathway. We believe that quercetin might prove to be a useful therapeutic component in treating cerebral I/R diseases in the near future.
The hypothalamus controls feeding behavior. Since central opioid systems may regulate feeding behavior, we examined the role of μ-, δ- and κ-opioid receptors in the lateral hypothalamus (LH), the hunger center, in feeding behavior of mice. Non-selective (naloxone; 3 mg/kg, s.c.) and selective μ- (β-funaltrexamine, β-FNA; 10 mg/kg, s.c.), δ- (naltrindole; 3 mg/kg, s.c.) and κ- (norbinaltorphimine, norBNI; 20 mg/kg, s.c.) opioid receptor antagonists significantly decreased food intake in food-deprived mice. The injection of naloxone (20 μg/side) into the LH significantly decreased food intake whereas the injection of naloxone (20 μg/side) outside of the LH did not affect food intake. The injection of β-FNA (2 μg/side), naltrindole (1 μg/side) or norBNI (2 μg/side) into the LH significantly decreased food intake. Furthermore, all of these antagonists significantly decreased the mRNA level of preproorexin, but not those of other hypothalamic neuropeptides. In addition, the injection of the GABAA receptor agonist muscimol (5 μg/side) into the LH significantly decreased food intake, and this effect was abolished by the GABAA receptor antagonist bicuculline (50 μg/side). Muscimol (1 mg/kg, i.p.) decreased the mRNA level of preproorexin in the hypothalamus. Naloxone (3 mg/kg, s.c.) significantly increased the GABA level in the LH and both bicuculline and the GABA release inhibitor 3-mercaptopropionic acid (3-MP, 5 μg/side) attenuated the inhibitory effect of naloxone on feeding behavior. 3-MP also attenuated the effects of β-FNA and norBNI, but not that of naltrindole. These results show that opioid systems in the LH regulate feeding behavior through orexin neurons. Moreover, μ- and κ-, but not δ-, opioid receptor antagonists inhibit feeding behavior by activating GABA neurons in the LH.
Free radicals and other so-called ‘reactive species’ are constantly produced in the brain in vivo. Some arise by ‘accidents of chemistry’, an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2 −). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2 − by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2 − formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, ‘catalytic’ iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2 −. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer’s disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.
Experimental studies have demonstrated that oxidative stress and apoptosis play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The purpose of this study was to determine whether the quercetin dihydrate (Q) protects against cerebral ischemia neuronal damage. Male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h and reperfused for 72 h. Quercetin (30 mg/kg, i.p) was administrated 30 min before the onset of ischemia and after the ischemia at interval of 0, 24, 48, and 72 h. The administration of Q showed marked reduction in infarct size, reduced the neurological deficits in terms of behaviors, suppressed neuronal loss and diminished the p53 expression in MCAO rats. Q was found to be successful in upregulating the antioxidant status and lowering the TBARS level. Conversely, the elevated activity of poly (ADP-ribose) polymerase (PARP), and activity of caspase-3 in MCAO group was attenuated significantly in Q treated group when compared with MCAO group. Our study reveals that Q, as a powerful antioxidant, could prevent free radicals associated oxidative damage and morphological changes in the MCAO rats. Thus, it may have a therapeutic value for the treatment of stroke.
Free radicals are known to cause secondary neuronal damage in cerebral ischemia/reperfusion (I/R). We investigated here the neuroprotective effect of resveratrol, a potent antioxidant present in grape seed, against cerebral I/R-induced mitochondrial dysfunctions in hippocampus. Transient rat middle cerebral artery occlusion (MCAO) model of brain ischemia was used to induce brain infarction. Resveratrol (10(-7) g/kg) was given twice intravenously: 15 min pre-occlusion and at the time of reperfusion (2 h post-occlusion). Resveratrol significantly restored ATP content and the activity of mitochondrial respiratory complexes in resveratrol treated group which were severely altered in MCAO group. Western blot analysis showed a marked decrease in cytochrome c release as a result of resveratrol treatment. Electrophoretic migration of hippocampal genomic DNA showed a marked decrease in DNA fragmentation after resveratrol treatment. Notably, expression of Hsp70 and metallothionein (MT) was significantly higher in MCAO group but their expression was more significant in resveratrol treated group. The status of mitochondrial glutathione (GSH), glucose 6-phosphate dehydrogenase (G6-PD) and serum lactate dehydrogenase (LDH) was restored by resveratrol treatment with a significant decrease in mitochondrial lipid peroxidation (LPO), protein carbonyl and intracellular H(2)O(2) content. Resveratrol significantly improved neurological deficits assessed by different scoring methods. Also, the brain infarct volume and brain edema were significantly reduced. Histological analysis of CA1 hippocampal region revealed that resveratrol treatment diminished intercellular and pericellular edema and glial cell infiltration. The findings of this study highlight the ability of resveratrol in anatomical and functional preservation of ischemic neurovascular units and its relevance in the treatment of ischemic stroke.
Melanocortin peptides (alpha-melanocyte-stimulating hormone, adrenocorticotropin and fragments thereof) have been shown to have numerous effects on the central nervous system, including recovery from nerve injury and retention of learned behaviour, but the mechanism of action of these peptides is unknown. A family of five melanocortin receptors have recently been discovered, two of which (melanocortin-3 and melanocortin-4 receptors) have been mapped in the rat brain. We have tested the hypothesis that the expression of one or more of the messenger RNAs for three melanocortin receptors (melanocortin-3, melanocortin-4 and melanocortin-5 receptors) would be altered in rat brain following unilateral transient hypoxic-ischaemic brain injury. In this study, using in situ hybridization, we show that melanocortin-4 receptor messenger RNA was up-regulated in the striatum in the non-damaged hemisphere within 24 h after severe hypoxic-ischaemic injury compared with control brains (P<0.05). In a small group of animals, this induction was not blocked by treatment with the anticonvulsant, carbamazepine. Expression of melanocortin-3 receptor messenger RNA in the brain was not altered in this hypoxic-ischaemic injury model and melanocortin-5 receptor messenger RNA was not detected in either control or hypoxic-ischaemic injured rat brains. We hypothesize that the up-regulation of melanocortin-4 receptor messenger RNA expression in the contralateral striatum may be involved in transfer of function to the uninjured hemisphere following unilateral brain injury.
Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.
The ladder rung walking test is a new task to assess skilled walking and measure both forelimb and hindlimb placing, stepping, and inter-limb co-ordination. Rats spontaneously walk from a starting location to a goal along a horizontal ladder. The spacing between the rungs of the ladder is variable and can be changed to prevent the animal from learning either the absolute or relative location of the rungs. The testing procedure requires minimal training and allows detailed quantitative and qualitative analysis using video recording. The utility of the test is described with postoperative data obtained from animals with unilateral neocortical strokes produced by pial stripping over the motor cortex, neonatal and adult unilateral corticospinal tract lesions produced by tract section at the pyramids, and unilateral dopamine depletions produced by injection of 6-hydroxydopamine into the nigrostriatal bundle. In addition, a group of aged rats was examined. Deficits in limb placing, stepping and co-ordination displayed by the animals demonstrate that this test can discriminate between lesions of the motor system or age-associated impairments. The test is useful for assessing loss and recovery of function due to brain or spinal cord injury, the effectiveness of treatment therapies, as well as compensatory processes through which animals adapt to nervous system injury.
The effects of different levels of quercetin on the blood pressure were studied in 6-week-old male Sprague-Dawley rats. The rats were fed with a control diet or a high-fat high-sucrose (HFS) diet containing 0, 0.02, 0.07, 0.2, or 0.5% quercetin for 4 weeks. The systolic blood pressure and the lipid peroxides in the plasma were both higher in the rats fed with the HFS diet without quercetin than in the rats fed with the control diet. The nitric oxide synthase (NOS) activity in the vascular tissues and nitric oxide (NO) metabolites in the plasma and urine were both lower in these rats. A distinct depression of the increase in blood pressure was found in the rats fed with the HFS diets containing quercetin. Each level of quercetin examined was effective, the 0.5% level being much more effective than other levels. Dietary quercetin decreased lipid peroxidation in the plasma of the rats fed with the HFS diets. Quercetin also suppressed the decrease in NO metabolites in the plasma and urine, and the NOS activity in the vascular tissues of these rats. These results suggest that the increased NO availability caused by the elevated NOS activity, and the antioxidative activity in these rats fed with quercetin may be sources of the antihypertensive effect of quercetin.
Batteries of behavioural tests provide a method by which researchers may examine specific functional pathways. The narrow beam test examines the ability of a rat to cross a narrow, elevated beam of wood or other material. In order to determine the utility of the narrow beam test in the study of Parkinsonism, it was of interest to characterise the performance of animals at this task. Rats were placed at one end of a 105 cm long, elevated beam and both the time it took to begin crossing the beam, as well as the total time taken to cross the beam, were measured. The effects of training, time of day and 6-hydroxydopamine lesion on beam performance were examined. Rats reached maximal performance at the task within a single test session and time of day had no effect on beam performance. Parkinsonian rats demonstrated a four-fold increase in both the latency to initiate the task and the total time to cross the beam (p < 0.05).