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Is there a role for curcumin in the treatment of bipolar disorder?
Abstract
Curcumin is a polyphenolic nonflavonoid compound extracted from the rhizome of turmeric (Curcuma longa), a plant commonly used in Indian and Chinese traditional medicine to treat rheumatism, cough, inflammation and wounds. Curcumin putative targets, known based on studies of diverse central nervous system disorders other than bipolar disorders (BD) include several proteins currently implicated in the pathophysiology of BD. These targets include, but are not limited to, transcription factors activated by environmental stressors and pro-inflammatory cytokines, protein kinases (PKA, PKC), enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Bcl-XL). Herein, we review previous studies on the anti-inflammatory and anti-oxidant properties of curcumin and discuss its therapeutic potential in BD.
... In the last decades, there has been a gradually increasing trend towards traditional medicine and phytochemicals for the treatment of chronic diseases [75]. The effect of curcumin on the outcome of mood swings in people with BD, although not widely studied in humans, may exhibit positive outcomes [68,76]. The international literature has demonstrated curcumin's involvement in BD molecular pathways. ...
... The international literature has demonstrated curcumin's involvement in BD molecular pathways. More to the point, curcumin, has shown an ability to interact with diverse biomolecules and increase BDNF levels, also reducing interleukin levels and oxidative stress in people with BD [76]. The BDNF signaling pathway in the hippocampus has been involved in the mechanism of neurogenesis and neuroprotection that preserves homeostasis and provides neuronal survival in humans [77]. ...
... The hippocampus is also suggested as a key target for the anti-stress effect of curcumin in both rodents and humans [12,78]. Remarkably, there is strong evidence that curcumin is a major modulator of pro-inflammatory enzymes such as lipoxygenases and cyclooxygenases (COX) as well as certain transcription factors [76]. Curcumin is involved in the signal transmission of inflammatory mediators like IL-6 and IL-1b and it is not only capable of suppressing COX-2 but also further regulates COX-2 gene expression [79]. ...
Background: Mental disorders in terms of depression, anxiety, and stress are one of the major causes of burden globally. Over the last two decades, the use of plant-based substances in the treatment of mental disorders in combination or not with medication has increasingly attracted the interest of the scientific research community. However, even if there is a plethora of naturally occurring bioactive compounds, most of them have low bioavailability, rendering them unable to insert into the bloodstream to exert their biological activities. Methods: This is a comprehensive narrative review that critically summarizes and scrutinizes the new approaches to the treatment of mental disorders using curcumin, also highlighting its bioavailability properties. The most accurate were searched using effective and relevant keywords. Results: This narrative review reveals substantial evidence that curcumin can exert significant effects on several mental disorders. However, despite the low cost, the extensive and confirmed potency of curcumin and its involvement in signaling pathways and the scientifically confirmed data regarding its molecular mechanisms of action against mental disorders, this naturally occurring compound presents low oral bioavailability. Pharmaceutical technology has provided solutions to increase the bioavailability of curcumin. Combination with piperine, galactomannosides, liposomal formulation or nanoformulation overcomes the bioavailability and solubility disadvantages. Conclusions: Although curcumin demonstrates anti-anxiety, anti-depressive and anti-stress properties, studies on humans are limited and heterogeneous. Further research is highly recommended to determine the most functional formula, dose, duration, and possible side effects of curcumin on mental disorders in humans. Based on the current knowledge, the curcumin nanoformulation and Theracurmin, a form of colloidal submicroscopic particles, seem to be the most effective bioavailable formulations, which may be examined in future clinical human studies.
... It has also long been used in complementary and alternative medicine (CAM) for its anti-oxidant and antiinflammatory properties (Maheshwari et al., 2006). In recent years, curcumin has been investigated in mainstream medicine for use in Alzheimer's and Parkinson's disease, cardiovascular diseases, cancer and psychiatric disorders (Aggarwal and Harikumar, 2009;Aggarwal and Sung, 2009;Brietzke et al., 2013;Maheshwari et al., 2006;Sookram et al., 2011). Curcumin was recently reviewed for its potential use with MDD (Lopresti et al., 2012) and BD (Brietzke et al., 2013). ...
... In recent years, curcumin has been investigated in mainstream medicine for use in Alzheimer's and Parkinson's disease, cardiovascular diseases, cancer and psychiatric disorders (Aggarwal and Harikumar, 2009;Aggarwal and Sung, 2009;Brietzke et al., 2013;Maheshwari et al., 2006;Sookram et al., 2011). Curcumin was recently reviewed for its potential use with MDD (Lopresti et al., 2012) and BD (Brietzke et al., 2013). In brief, these reviews discuss how curcumin is a compound with low toxicity and multiple targets that has shown great promise in epidemiologic and pre-clinical studies, showing effects of decreasing cytokines, stabilizing HPA activity, decreasing oxidative stress and improving mood symptoms in animal models, however, to date has yet been tested in clinical trials (Brietzke et al., 2013;Lopresti et al., 2012). ...
... Curcumin was recently reviewed for its potential use with MDD (Lopresti et al., 2012) and BD (Brietzke et al., 2013). In brief, these reviews discuss how curcumin is a compound with low toxicity and multiple targets that has shown great promise in epidemiologic and pre-clinical studies, showing effects of decreasing cytokines, stabilizing HPA activity, decreasing oxidative stress and improving mood symptoms in animal models, however, to date has yet been tested in clinical trials (Brietzke et al., 2013;Lopresti et al., 2012). Therefore, curcumin presents as another appealing, potential therapeutic agent in need of further evaluation to determine efficacy and appropriate dosage. ...
Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy.
... The antioxidant, anti-in ammatory, anti-proliferative, antiseptic, analgesic, anti-malarial, antitumoral, apoptosis-inducing, and anti-angiogenesis properties of Cur have been reported [10]. All appear to involve the inhibition of NFk B signaling, which lowers pro-in ammatory cytokines IL-1, IL-6, and TNF-α [11]. In an alcoholic animal neuropathy model, Cur antagonized the cellular consequences of oxidative stress by preventing DNA damage [12]. ...
... In an alcoholic animal neuropathy model, Cur antagonized the cellular consequences of oxidative stress by preventing DNA damage [12]. Curcumin may be a promising remedy for certain NDDs [11,13,14]. ...
A curcumin-conjugated MgO nanostructure (Cur/MgO NPs) was synthesized, and its composition was verified. XRD and a particle size analyzer were used to determine the average crystalline and particle sizes. Morphological studies were conducted using FE-SEM. UV-Vis was also employed to examine absorption patterns, and FT-IR spectroscopy analyzed the functional groups involved in the reaction. The following protocol evaluated the effectiveness of Cur/MgO NPs in ketamine-treated male BALB/c mice. Group 1 received 0.2 mL of normal saline. Group 2 animals received Ket (25 mg/kg). Group 3 animals received 40 mg/kg Cur and 25 mg/kg Ket. Groups 4–6 received Ket (25 mg/kg) and Cur/MgO N.P.s (10, 20, or 40 mg/kg). Group 7 received 5 mg/kg MgO and Ket (25 mg/kg). Mice were injected ip daily for two weeks. The hippocampal tissue was analyzed for oxidative stress, inflammation, apoptotic markers, and mitochondrial quadruple complex enzymes. The Cur/MgO N.P.s were neuroprotective against the inflammation, apoptosis, and oxidative stress induced by Ket.
... The socio-economic impact of bipolar disorders extends beyond individual suffering, posing challenges to employment, social relationships and overall well-being [3,4] . While conventional treatments, including pharmacotherapy and psychotherapy play pivotal roles, their efficacy is often accompanied by limitations, prompting a growing interest in Complementary and Alternative Medicine (CAM) [5,6] . In this landscape, traditional herbal medicine emerges as a promising frontier for addressing the complexities of bipolar disorder. ...
... 19 The role of curcumin in the management of depression and bipolar disorder has been proposed recently. 20 Curcumin as an add-on to antidepressant drugs has been convincingly shown to reduce depressive symptoms, compared to placebo add-on. A recent meta-analysis supported the utility of adjunctive curcumin in the management of depression and anxiety disorders. ...
Nutraceutical agents and food supplements are commonly used as treatment adjuncts in neuropsychiatric disorders. Curcumin, a bioactive agent obtained from the rhizome of Curcuma longa, with its antioxidant and anti-inflammatory properties, has gained much research attention in the last few decades. In this narrative review, we intend to summarize the evidence available for curcumin as an add-on agent in the management of schizophrenia. We searched PubMed/EBSCO for both human and animal trials utilizing curcumin in the management of schizophrenia. We obtained ten articles (five preclinical and five clinical) from the focused literature search. Clinical research utilizing curcumin in schizophrenia is limited to negative and cognitive symptoms. Available preclinical studies suggest curcumin’s utility in ameliorating extrapyramidal and metabolic side effects when given as an adjunct with antipsychotics. Curcumin, as an add-on agent, appears promising to improve the negative and cognitive symptoms of schizophrenia. Notably, curcumin was tolerable and safe in all the randomized human clinical trials. The poor oral bioavailability is, however, a limiting factor in its widespread use.
... The authors concluded that curcumin prevented oxidative damage, demonstrating its therapeutic potential in prophylactic interventions during the manic phase (Gazal et al. 2014a). Notably, curcumin regulates multiple targets that include transcription factors activated by environmental stressors and proinflammatory cytokines, protein kinases, enzymes, growth factors, inflammatory mediators, and anti-apoptotic proteins (Brietzke et al. 2013). Moreover, this compound has been studied in different disorders in preclinical models, such as Alzheimer's disease and Parkinson's disease, and has demonstrated significant neuroprotective potential (Bassani et al. 2017;Sharma and Nehru 2018). ...
Bipolar disorder (BD) is a complex psychiatric disease characterized by mood swings that include episodes of mania and depression. Given its cyclical nature, BD is especially hard to model; however, the standard practice has been to mimic manic episodes in animal models. Despite scientific advances, the pathophysiology of BD is not fully understood, and treatment remains limited. In the last years, natural products have emerged as potential neuroprotective agents for the treatment of psychiatric diseases. Thus, the aim of this review was to explore the therapeutic potential of natural compounds and derivatives against BD, taking into account preclinical and clinical studies. Reliable articles indexed in databases such as PubMed, Web of Science and Science Direct were used. In clinical studies, treatment with herbal plants extracts, omega-3, inositol, n-acetylcysteine and vitamin D has been associated with a clinical improvement in symptoms of mania and depression in BD patients. In animal models, it has been shown that red fruits extracts, curcumin, quercetin, gallic acid, alpha-lipoic acid and carvone can modulate many neurochemical pathways involved in the pathophysiology of manic episodes. Thus, this review appointed the advances in the consumption of natural compounds and derivatives as an important therapeutic strategy to mitigate the symptoms of BD.
... It has anti-inflammatory, antioxidant, anti-aging, antiviral and anti-carcinogenic properties [2][3][4]. Numerous studies have been carried out in order to unveil its proficiency in treatment and prevention of a number of health issues [5,6]. Curcumin is proved to be non-toxic to human upon consumption in larger amounts [7,8]. ...
Curcumin, a hydrophobic polyphenol found in rhizome of turmeric (curcuma longa) is one of the generally used spice in Asian countries. It has been found through studies that it has numerous health promoting properties and is proved to have curative properties as it possesses antioxidant and anti-inflammatory properties. Due to low oral bioavailability, decreased solubility, quick metabolism and removal from body, it is challenging to achieve maximum benefits from it. This study was aimed to enhance curcumin oral bioavailability by making use of nanoencapsulation technique. Biodegradable nanocapsules were prepared by consecutive addition of food grade polyelectrolytes including OSA-modified starch (PGU), as an emulsifier, chitosan and sodium-carboxymethylcellulose by ultrasonication technique using primary nanoemulsion as template. Results showed that the mean droplet diameter of nanocapsules was 160.57 ± 1.06 nm, the average PDI was 0.14 ± 0.01 and average charge was recorded as -24.43 ± 0.49 mV. Microscopy results showed that the nanostructures were spherical in shape having mean droplet diameter below 200nm. The nanocapsules assessment as a carrier in enhancing the in vivo oral bioavailability of curcumin was made; however, further studies and better tools are needed to clearly know the potential of developed nanosystem.
... Curcumin helps in treatment of anxiety and depression by alleviating interlinked symptoms (Lopresti, Maes et al., 2014). Curcumin increase the level of fatty acid Omega-3 that motivates the development of brain (Brietzke, Mansur et al., 2013). ...
Curcumin is a poly belongs to the Zingiberaceae family. In developing countries, turmeric and its products are consumed to overcome many ailments because of cost effectiveness. It is frequently used in herbal medicine. It shows strong therapeutic potential as antioxidant, anti plays a prominent role in management of many diseases and disorders diabetes, diabetic micro Intestin infection and inflammation. It is safe to use and shows no side effects or toxicity but sometimes it can cause low fertility, bleeding disorders, low glucose level and heavy menstruat diseases.
... 17 It increase the levels of omega-3 fatty acid that promotes the development of brain. 18 ...
... However, the mechanisms involved in these effects should be evaluated in preclinical trials and more clinical studies need to be conducted to further reinforce this notion. The potential use of curcumin in bipolar disorder was proposed in revision papers by Brietzke et al. (2013) and Ong et al., (2015), especially due to its anti-inflammatory, antioxidant and neurotrophic properties. In preclinical models, ketamine administration is capable to induce hyperlocomotion and other behavioral and neurochemical changes in rats that resemble schizophrenia-like states and the manic episode of bipolar disorder. ...
Considering the high prevalence of psychiatric disorders, its social burden and the limitations of currently available treatments, alternative therapeutic approaches targeting different biological pathways have been investigated. Curcumin is a natural compound with multi-faceted pharmacological properties, interacting with several neurotransmitter systems and intracellular signaling pathways involved in mood regulation. Also, curcumin has anti-inflammatory, antioxidant and neurotrophic effects, suggesting a strong potential to manage conditions associated with neurodegeneration, such as psychiatric disorders. Most literature data focused on the potential of curcumin to counteract behavioral and neurochemical alterations in preclinical models of depression. The findings still need to be further explored and clinical reports share some controversial results that might be associated with its low systemic bioavailability following oral administration. Other psychiatric disorders also have neurochemical alterations similar to those found in depression, including neurotoxicity, oxidative stress and neuroinflammation. Despite the limited number of reports, preclinical models investigated the potential role for curcumin in anxiety, bipolar disorder, post-traumatic stress disorder and autism spectrum disorders. Here, we will summarize the cellular targets of curcumin relevant to psychiatric disorders and its effects in preclinical and clinical studies with depression, anxiety disorders and other psychiatric related conditions.
... This rearing behavior in OVX and curcumin-treated rats was consistently observed both in EPM (figure 1) as well as open field tests (data not shown). Previous data point to the positive effects of curcumin against different behavior disturbances [43, 44]. Our results show the benefits of curcumin oral administration against anxiety-like behavior and brain oxidative damage induced by ovariectomy. ...
Menopause occurs gradually and is characterized by increased susceptibility to developing mood disorders. Several studies have suggested treatments based on the antioxidant properties of vitamins and herbal compounds as an alternative to hormone replacement therapies, with few or none reporting toxicity. The present study was performed to explore the effects of curcumin oral supplementation on anxiety-like behavior and oxidative stress parameters in different central nervous system (CNS) areas of ovariectomized (OVX) rats. Female Wistar rats were randomly divided into either sham-operated or OVX groups. Sham-operated group (n = 8) and an OVX group (n = 11) were treated with vehicle, and the other two OVX groups received curcumin at 50 or 100 mg/kg/day doses (n = 8/group). Elevated plus maze (EPM) test was performed on the 28th day of treatment. On the 30th day, animals were killed and the dissected brain regions were removed and stored at − 80°C until analysis. Ovariectomy induced deficit in the locomotor activity and increased anxiety-like behavior. Moreover, OVX rats showed increased lipid oxidized in the frontal cortex and striatum, increased hippocampal and striatal carbonylated protein level, and decreased striatal thiol content of non-protein fraction indicative of a glutathione (GSH) pool. Curcumin oral treatment for 30 days reduced oxidative stress in the CNS areas as well as the behavior alterations resulting from ovariectomy. Curcumin supplementation attenuated most of these parameters to sham comparable values, suggesting that curcumin could have positive effects against anxiety-like disturbances and brain oxidative damage due to hormone deprivation.
... Similar results have been found for the newer biologic psoriasis treatment ustikinumab, which targets IL-12 and IL-23 (Langley et al., 2010). Complementary and alternative medicines that possess anti-inflammatory properties including omega-3 polyunsaturated fatty acids (recently reviewed (Mcnamara and Strawn, 2013; Su et al., 2013; Grosso et al., 2014)) and curcumin (for MDD (Lopresti et al., 2012; Lopresti et al., 2014) and BD (Brietzke et al., 2013)). Notably, Raison et al. (2013) showed that infliximab had an antidepressant effect on individuals who had elevated TNF-and CRP but not in those with normal CRP and TNF-levels (Raison et al., 2013). ...
Evidence supports inflammatory involvement in mood and cognitive symptoms across psychiatric, neurological and medical disorders; however, inflammation is not a sensitive or specific characteristic of these diagnoses. The National Institute of Mental Health Research Domain Criteria (RDoC) ask for a shift towards a neurobiological focus in the study of of brain illnesses rather than symptom-based diagnoses, which may provide a useful framework for integrating the effects of inflammation on brain function. Based on preclinical and clinical findings, relevant relationships span negative and positive valance systems, cognitive systems, systems for social processes and arousal/regulatory systems. As an exemplar, we discuss the psychopathological domain of anhedonia across brain disorders, conceptualizing the relevance of inflammation (e.g. cellular immunity) and downstream processes (e.g. indoleamine 2,3-dioxygenase activation and oxidative inactivation of tetrahydrobiopterin) across RDoC units of analysis (e.g. catecholamine neurotransmitter molecules, nucleus accumbens medium spiny neuronal cells, dopaminergic mesolimbic and mesocortical reward circuits, animal paradigms, etc.). We discuss potential implications of the RDoC matrix informing the mechanistic role of inflammation in brain illnesses.
... Gazal et al. (2014) reported that curcumin prevented the behavioral and pro-oxidant effects induced by ketamine in rats, suggesting that curcumin might be an attractive compound for preventive intervention in BD by reducing the episode relapse and the oxidative damage associated with mania. The positive outcomes of curcumin were also observed in various animal models for major depression (Kulkarni et al., 2009;Brietzke et al., 2013). ...
... N-acetyl cysteine (NAC) is a glutathione precursor with anti-oxidative and anti-infl ammatory functions (Asevedo et al. 2012 ); it has antidepressant effi cacy in bipolar disorder, suggesting a potential role in MDD (Berk et al. 2008 ; Magalhaes et al. 2011 ). Curcumin is a substance extracted from a plant used in Asian culinary with anti-infl ammatory and anti-oxidative effects (Brietzke et al. 2013 ) and shows promising results in animal models (Kulkarni et al. 2009 ; Xu et al. 2005 ) and depressed people as well (Lopresti et al. 2014 ). Finally, ketamine and zinc are glutamate-NMDA antagonists, with actions on neurotransmitter circuits and the immune-infl ammatory system as well. ...
Major depressive disorder (MDD) is a high prevalent mental disorder. Several lines of evidence have demonstrated that MDD is accompanied by cell-mediated immune (CMI) activation and a chronic mild inflammatory response, characterized by an increased production of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Immune-inflammatory pathways are involved in the onset of depressive symptoms and partly explain the high comorbidity of MDD and general medical diseases. Moreover, antidepressants have anti-inflammatory and negative immunoregulatory effects, while anti-inflammatory agents may improve depressive symptoms. Despite the large evidence describing activated immune-inflammatory responses in MDD, the pathophysiological mechanisms are unclear yet. Future studies should examine the clinical implications of those findings by targeting immune-inflammatory pathways as a therapeutic tool for individuals with MDD.
... However to date few systematic evaluations have assessed the efficacy of add-on anti-inflammatory treatment for the depressive and manic episodes of BPAD. Works to date have evaluated the therapeutic use of, respectively, aspirin (Berk et al., 2013), omega-3 fatty acids (Balanzá-Martínez et al., 2011; Montgomery and Richardson, 2008), and curcumin (Brietzke et al., 2013) in BPAD; but, overall, provide limited evidence, in part due to methodological study criteria, and also hindered by a focus on single agents., 1992 ) or Diagnostic and Statistical Manual of Mental Disorders (DSM-V; American Psychiatric Association, 2013, or previous versions of these diagnostic manuals) were included. Although there are data demonstrating that the inflammatory profile of children and adolescents converges with that of adults (Mitchell and Goldstein, 2014), they were excluded from this review in an attempt to minimize confounders. ...
Inflammation has emerged as a potentially important factor - and thus putative pharmacological target - in the pathology of bipolar disorders. However to date no systematic evaluations of the efficacy of add on anti-inflammatory treatment for the depressive and manic episodes have been carried out.
Sixteen articles were ultimately identified - by computer searches of databases (including PsycINFO, MEDLINE, and EMBASE), supplemented by hand searches and personal communication - as meeting study inclusion criteria.
Anti-manic effects were evaluated in two trials, one of adjunctive n-acetyl cysteine (NAC), one of omega-3 fatty acids (O3FA), and significant improvements only emerged for NAC. Celecoxib had a rapid but short-lived antidepressant effect. Despite limited effects of O3FA on symptoms, imaging data demonstrated alterations in neuronal functioning that might have longer-term therapeutic effects. Evidence was strongest for adjunctive NAC in bipolar depression though conclusions are limited by small sample sizes.
Definitive conclusions are limited by the paucity of data, small study sizes, and the variability in methodology used.
Current evidence for aspirin or celecoxib is insufficient though further investigation of the potential of celecoxib in early illness onset is warranted. Variable evidence exists for add-on O3FA though an indication of short-term treatment effects on membrane fluidity and neuronal activity suggest longer follow-up assessment is needed. The strongest evidence emerged for NAC in depression and future studies must address the role of illness duration and patients׳ baseline medications on outcomes. Careful consideration of lithium toxicity in the elderly and renal impaired is essential.
Copyright © 2014 Elsevier B.V. All rights reserved.
... Curcumin is a compound extracted from turmeric (Curcuma longa) and is commonly used as a culinary seasoning in different regions of Asia. Curcumin is believed to act in inflammatory, oxidative and apoptotic pathways [79] . To our knowledge, curcumin has not been used in clinical trials for depression so far. ...
In the last decades convergent findings from several lines of evidence has revealed a robust association between major depressive disorder (MDD) and inflammatory pathways. Despite this, the translation of these findings into new and better treatments for MDD has not occurred. The objective of this study is to comprehensively review what is already known with reasonable certainty on inflammatory pathways in MDD, to clarify some points that have been insufficiently studied and to discuss the implications of these findings for future studies targeting inflammatory pathways as a therapeutic tool for individuals with MDD. © 2014 S. Karger AG, Basel.
... Besides that, curcumin administration improves memory function, cerebral blood flow and energy metabolism (Rajasekar et al., 2013) and enhances the levels of brain derived neurothrophic factor (BDNF) and hippocampal neurogenesis (Xu et al., 2007). A recent work discussed that by acting in all those cellular targets, curcumin might be a compound of interest to treat the mood and cognitive impairments associated with BD (Brietzke et al., 2013). Here, we were able to test, for the first time, an confirm the potential of curcumin against behavioral alteration and oxidative stress in an animal model of mania. ...
The experimental work and design on the creation and enhanced of a quetiapine fumarate nanostructured lipid transport system for oral drug delivery of used for disease treatment of Schizophrenia. Because quetiapine fumarate is a substrate for Para-glycoprotein inhibitors organize on the surface of the gut and endothelial cells of the BBB. An inhibitor of curcumin is used as drug aid substance entrance to these cells. It was also planned to increase the drug's bioavailability, as it belongs to biopharmaceutical categorization system class II and has a low oral bioavailability of 9%, with a low dose so that the drug's negative effects could be avoided. Hot homogenization method was used to design nanostructured lipid transport systems from cholesterol and oleic acid prepared from different types of lipids one is solid lipid and liquid lipid, respectively. Various types of Surfactant are used in the formulation of nano structured lipid transport system that is vitamin E, tocopherol and polyethylene glycol succinate, which has frequent properties. The primary aim was to enhanced lipid concentration through various experimental design. The respondent were simultaneously charcterized using Deringer's desirability function, which yielded a desirability value of D 0.893, indicating a high degree of global optimisation. To evaluate quetiapine fumarate and curcumin in formulations, a simultaneous approach using RP-HPLC was devised. The configuration of nanostructured lipid transport were characterised for several physiochemical properties, as well as the influence of cholesterol and oleic acid on particle size and transparency. Ex vivo permeability tests were performed to examine the effect of curcumin when coupled with quetiapine fumarate.
Background
Inflammatory processes play a role in the etiopathogenesis of bipolar disorder type 1. Full therapeutic responses are seldom seen and the ongoing inflammatory processes in the brain could lead to neuronal loss. Curcumin, a relatively safe herbal compound, has been shown to have anti-inflammatory effects. The present randomized double-blind clinical trial study aimed to investigate the effect of adding curcumin to the treatment regimen of BID.
Materials and methods
This randomized double-blind clinical trial was conducted on 78 patients diagnosed with BID according to the Diagnostic and Statistical Manual of Mental Disorders (DSM 5) criteria. The sample were divided into two groups. Patients in both groups received sodium valproate starting at a dose of 600 milligrams per day and administered up to 20 milligrams per kilogram per day or the highest dosage of the patient’s tolerance. Patients in the intervention group also received curcumin as nanomicelle in soft gelatin capsules 40 milligrams per day. The control group received placebo tablets with the same characteristics as the curcumin tablets. They were assessed by a psychiatrist using the Young Mania Rating Scale (YMRS), Mini-Mental State Examination (MMSE), Clinical Global Impression (CGI), and a medication side effect questionnaire at the beginning of the study, as well as in the first, second, and fourth weeks of the study.
Results
Among the 78 patients chosen to participate in the project, 54 people completed the trial. No specific side effect was observed in the two groups. Both groups showed an increase in their MMSE scores compared to the beginning of the study (value of p < 0.001). Although this increase was not statistically different between the two groups (value of p = 0.68). The YMRS score of both groups decreased significantly by the end of the study (value of p < 0.001); however, this decrease was not significantly different between the two groups (value of p = 0.64). In addition, the two groups experienced a significant increase in their CGI scores throughout the study (value of p < 0.001), this increase however was not statistically different between the two groups (value of p = 0.88).
Conclusion
The present study suggested that curcumin may not be a useful adjuvant agent in the management of patients with BID receiving sodium valproate as treatment.
Clinical trial registration: Iranian Registry of Clinical Trials (IRCT), identifier IRCT2016102530504N1.
Curcumin is a polyphenolic active ingredient found in the Curcuma Longa plant (Turmeric). It is a member of the Zingiberaceae family. Turmeric and its compounds are used to treat a variety of diseases in underdeveloped nations because to their low cost. It's a common ingredient in herbal medicine. As an antioxidant, antifungal, antibacterial, anti-inflammatory, and anti-cancer agent, it has a lot of promise. Diabetes mellitus, arthritis, diabetic microangiopathy, gastro-intestinal illness, psoriasis, diabetic nephropathy, anxiety, bacterial infection, hyperlipidemia, acute cardiac disease and inflammation are only of few the disorders and symptoms for which it is very helpful. Although curcuma longa is safe to use and has no negative effect or any toxic response on human health, it is best known for its positive effect in reducing infertility, lowering blood glucose level, reduce bleeding issue and heavy menstruation in some people. Curcumin is an anti-oxidant that played a vital role in the prevention of many illnesses.
We synthesized silica nanoparticles by using a straightforward chemical method. UV-VIS spectroscopy confirms the primary characterization of curcumin (CU) at 420nm, silica nanoparticles (SiNPs) at 337nm and two peaks at 310 and 418nm, conjugates curcumin-silica nanoparticles (CU-SiNPs) at 417nm were observed. FTIR confirm the diarylheptanoid chromophore group of both curcumin and after the formation of the conjugate, which confirms the successes of formation. Curcumin had several distinct peaks in its XRD pattern due to its crystalline nature, whereas silica nanoparticles had the typical amorphous pattern. Curcumin crystallinity is retained after conjugation CU-SiNPs but the intensity of the peaks has decreased. Drosophila melanogaster was used to assess any toxic effects of curcumin, silica nanoparticles and their nanoconjugates on life-history traits after successful conjugations. D. melanogaster were given 10mg L⁻¹ doses of CU, SiNPs and CU-SiNPs treated food medium, while the control group received normal food medium. The life history characteristics of fertility, hatchability and development time in D. melanogaster were examined. In all repetitions, the range of eggs/fly/day 61-63 was comparable in both experimental and control flies given 10mg L-1 doses. Furthermore, the control sample had 100% hatchability, whereas the experimental group had 99-100% hatchability. The DOD of the control group and all combinations of experimentally treated flies were nearly the same, e.g. 251hr. Overall, curcumin, as well as other synthesized nanoparticles and their conjugates, has a high bioavailability and without toxicity.
Depressive and anxiety disorders affect a significant proportion of the global population and constitute one of the highest disease burdens worldwide. Conventional pharmacological treatments are traditionally the first line of therapy for individuals affected by these conditions although these are only successful approximately half of the time and are often associated with undesirable side effects. This review describes the use of the natural substance curcumin as a potential alternative treatment of these mental disorders. With this in mind, we analyzed the effects of curcumin in eight clinical studies of depression and five studies of anxiety and assessed these using psychiatric symptom scores and molecular biomarker readouts.
Approved pharmacological treatments for bipolar disorder (BD) include conventional mood stabilizers and antipsychotic medications. Pharmacological interventions remain the mainstay of BD treatment; however, clinical outcomes remain unacceptably poor with high rates of relapse, treatment resistance, persistent functional impairment, suicidality, and decreased life expectancy. Therefore novel pharmacological treatments are urgently needed. New interventions may target novel neurotransmitter systems (e.g., outside of serotonin, norepinephrine, dopamine, and GABA), such as glutamate, opioid, circadian rhythm, and cholinergic systems. Of these, modulation of the glutamate system has shown the most promise with ketamine demonstrating rapid and robust antidepressant effects in bipolar and unipolar depression. Nonneurotransmitter systems have also been targeted, with emerging and converging evidence implicating inflammation, oxidative stress, abnormal insulin signaling, and the gut-microbiota in the pathophysiology of BD. Antiinflammatory agents have been particularly promising; however, clinical trial results have been mixed. Subgrouping and sample stratification will likely be key strategies for effectively developing future novel interventions, matching the treatment target with underlying pathophysiology on an individual patient level.
Background: Inflammatory processes in the brain play an important role in etiopathogenesis of many psychiatric disorders including, bipolar mood disorder (BMD) as a life-long episodic disease. An inefficient therapeutic intervention especially for resistant cases makes the necessity of doing more precise investigation to find out new therapeutic approaches apparent. This double-blind study aims to investigate the effect of Crucumin as anti-inflammatory herbal based drug in the treatment of BMD.
Results: 78 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for BMD screening to participate in the trial. The participants included 32 patients in the placebo group receiving sodium valproate and crucumin and 38 patients in the control group receiving placebo and sodium valproate. At the beginning of the study and weeks 1, 2, 4 the patients were assessed by a psychiatrist using Young mania score (YMRS). Fifty four patients completed the trial. Mean age in patients group was 36.28±10.73 and in control group was 32.42 ±9.60.Clinical characteristics of the patients, such as age, did not differ between groups P value ≥0.05. Results showed the process of changes were significant different in both group. The results showed that the changes in the resultss of YMRS, MMSE and CGI scores were significant in each group (P value≤0.001), but no significant difference has been detected between the two groups (p≥0.05).
Conclusions: this study suggested that crucumin cannot be an effective adjuvant agent in management of patients with BMD under treatment with sodium valproate.
Rationale:
Immune dysfunction has been strongly implicated in the pathophysiology of bipolar disorder (BD). As such, numerous clinical trials have investigated the effects of anti-inflammatory agents in the treatment of BD.
Objectives:
Review clinical studies evaluating the effects of anti-inflammatory agents in the treatment of BD during all illness phases (e.g., depression, mania, and euthymia).
Methods:
Relevant databases were searched from inception to August 27, 2018 for clinical studies evaluating the effects of anti-inflammatory agents in BD.
Results:
The majority of identified clinical trials evaluated adjunctive anti-inflammatory agents in the acute treatment of bipolar depression, demonstrating antidepressant effects with N-acetylcysteine (NAC), pioglitazone, minocycline, and coenzyme Q10, along with mixed evidence for omega-3s, and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-manic effects of adjunctive anti-inflammatory agents have been minimally studied, with some promising preliminary results supporting potential anti-manic effects of adjunctive celecoxib and NAC. Maintenance studies are also limited, with inadequate evidence to support mood stabilizing effects of anti-inflammatories while euthymic. Regardless of illness phase, early results suggest that anti-inflammatory agents are likely most beneficial in the subgroup of BD with immune dysregulation.
Conclusions:
Several proof-of-concept clinical trials have shown promising results for anti-inflammatory agents in the treatment of bipolar depression with moderate effect sizes and good tolerability. The effects of anti-inflammatory agents during manic and euthymic periods remains uncertain. Future larger studies, using stratified samples, enriched for participants with immune dysfunction, are required to determine the role of immune modulating agents in the treatment of BD.
Curcumin, a yellow bioactive component of Indian spice turmeric is known to have a wide spectrum of biological applications. In spite of various astounding therapeutic properties, it lacks in bioavailability mainly due to its poor solubility in water. In this work, we have conjugated curcumin with silica nanoparticles to improve its aqueous solubility and hence to make it more bioavailable. Conjugation and loading of curcumin with silica nanoparticles was further examined with Transmission Electron Microscope (TEM) and Thermogravimetric Analyser. Cytotoxicity analysis of synthesized silica:curcumin conjugate was studied against HeLa cell lines as well as normal fibroblast cell lines. This study shows that silica:curcumin conjugate has great potential for anticancer application.
Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [14C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/ g of tissue, reflects differences in dietary concentration. [14C]Curcumin disappeared rapidly from tissues and plasma within 2?8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.
Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood. The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model. Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment. JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis. These pro-apoptosis effect can be diminished by curcumin. Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP. Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.
In many individuals with major neuropsychiatric disorders including depression, bipolar disorder and schizophrenia, their disease characteristics are consistent with a neuroprogressive illness. This includes progressive structural brain changes, cognitive and functional decline, poorer treatment response and an increasing vulnerability to relapse with chronicity. The underlying molecular mechanisms of neuroprogression are thought to include neurotrophins and regulation of neurogenesis and apoptosis, neurotransmitters, inflammatory, oxidative and nitrosative stress, mitochondrial dysfunction, cortisol and the hypothalamic-pituitary-adrenal axis, and epigenetic influences. Knowledge of the involvement of each of these pathways implies that specific agents that act on some or multiple of these pathways may thus block this cascade and have neuroprotective properties. This paper reviews the potential of the most promising of these agents, including lithium and other known psychotropics, aspirin, minocycline, statins, N-acetylcysteine, leptin and melatonin. These agents are putative neuroprotective agents for schizophrenia and mood disorders.
Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1-100 μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1 μg/mL). EF31 (IC(50)~5 μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC(50)~35 μM) and curcumin (IC(50) >50 μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC(50)~1.92 μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC(50)~131 μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development.
Our preliminary screening had shown that the curcumin derivative [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] or BDMC33 exhibited improved anti-inflammatory activity by inhibiting nitric oxide synthesis in activated macrophage cells. In this study, we further investigated the anti-inflammatory properties of BDMC33 on PGE(2 )synthesis and cyclooxygenase (COX) expression in IFN-γ/LPS-stimulated macrophages. We found that BDMC33 significantly inhibited PGE(2) synthesis in a concentration-dependent manner albeit at a low inhibition level with an IC(50) value of 47.33 ± 1.00 µM. Interestingly, the PGE(2) inhibitory activity of BDMC33 is not attributed to inhibition of the COX enzyme activities, but rather BDMC33 selectively down-regulated the expression of COX-2. In addition, BDMC33 modulates the COX expression by sustaining the constitutively COX-1 expression in IFN-γ/LPS-treated macrophage cells. Collectively, the experimental data suggest an immunodulatory action of BDMC33 on PGE(2) synthesis and COX expression, making it a possible treatment for inflammatory disorders with minimal gastrointestinal-related side effects.
Bipolar disorder (BD) is a debilitating syndrome that is often undiagnosed and undertreated. Population surveys show that persons with BD often self-medicate with complementary and alternative medicine (CAM) or integrative therapies in spite of limited research evidence supporting their use. To date, no review has focused specifically on nonconventional treatments of BD.
The study objectives were to present a review of nonconventional (complementary and integrative) interventions examined in clinical trials on BD, and to offer provisional guidelines for the judicious integrative use of CAM in the management of BD.
PubMed, CINAHL,(®) Web of Science, and Cochrane Library databases were searched for human clinical trials in English during mid-2010 using Bipolar Disorder and CAM therapy and CAM medicine search terms. Effect sizes (Cohen's d) were also calculated where data were available.
Several positive high-quality studies on nutrients in combination with conventional mood stabilizers and antipsychotic medications in BD depression were identified, while branched-chain amino acids and magnesium were effective (small studies) in attenuating mania in BD. In the treatment of bipolar depression, evidence was mixed regarding omega-3, while isolated studies provide provisional support for a multinutrient formula, n-acetylcysteine, and l-tryptophan. In one study, acupuncture was found to have favorable but nonsignificant effects on mania and depression outcomes.
Current evidence supports the integrative treatment of BD using combinations of mood stabilizers and select nutrients. Other CAM or integrative modalities used to treat BD have not been adequately explored to date; however, some early findings are promising. Select CAM and integrative interventions add to established conventional treatment of BD and may be considered when formulating a treatment plan. It is hoped that the safety issues and clinical considerations addressed in this article may encourage the practice of safety-conscious and evidence-based integrative management of BD.
Microglial cells are important effectors of the neuronal innate immune system with a major role in chronic neurodegenerative diseases. Curcumin, a major component of tumeric, alleviates pro-inflammatory activities of these cells by inhibiting nuclear factor kappa B (NFkB) signaling. To study the immuno-modulatory effects of curcumin on a transcriptomic level, DNA-microarray analyses were performed with resting and LPS-challenged microglial cells after short-term treatment with curcumin.
Resting and LPS-activated BV-2 cells were stimulated with curcumin and genome-wide mRNA expression patterns were determined using DNA-microarrays. Selected qRT-PCR analyses were performed to confirm newly identified curcumin-regulated genes. The migration potential of microglial cells was determined with wound healing assays and transwell migration assays. Microglial neurotoxicity was estimated by morphological analyses and quantification of caspase 3/7 levels in 661W photoreceptors cultured in the presence of microglia-conditioned medium.
Curcumin treatment markedly changed the microglial transcriptome with 49 differentially expressed transcripts in a combined analysis of resting and activated microglial cells. Curcumin effectively triggered anti-inflammatory signals as shown by induced expression of Interleukin 4 and Peroxisome proliferator activated receptor α. Several novel curcumin-induced genes including Netrin G1, Delta-like 1, Platelet endothelial cell adhesion molecule 1, and Plasma cell endoplasmic reticulum protein 1, have been previously associated with adhesion and cell migration. Consequently, curcumin treatment significantly inhibited basal and activation-induced migration of BV-2 microglia. Curcumin also potently blocked gene expression related to pro-inflammatory activation of resting cells including Toll-like receptor 2 and Prostaglandin-endoperoxide synthase 2. Moreover, transcription of NO synthase 2 and Signal transducer and activator of transcription 1 was reduced in LPS-triggered microglia. These transcriptional changes in curcumin-treated LPS-primed microglia also lead to decreased neurotoxicity with reduced apoptosis of 661W photoreceptor cultures.
Collectively, our results suggest that curcumin is a potent modulator of the microglial transcriptome. Curcumin attenuates microglial migration and triggers a phenotype with anti-inflammatory and neuroprotective properties. Thus, curcumin could be a nutraceutical compound to develop immuno-modulatory and neuroprotective therapies for the treatment of various neurodegenerative disorders.
In a previous three-month study of Meriva, a proprietary curcumin-phosphatidylcholine phytosome complex, decreased joint pain and improvement in joint function were observed in 50 osteoarthritis (OA) patients. Since OA is a chronic condition requiring prolonged treatment, the long-term efficacy and safety of Meriva were investigated in a longer (eight months) study involving 100 OA patients. The clinical end points (Western Ontario and McMaster Universities [WOMAC] score, Karnofsky Performance Scale Index, and treadmill walking performance) were complemented by the evaluation of a series of inflammatory markers (interleukin [IL]-1beta, IL-6, soluble CD40 ligand [sCD40L], soluble vascular cell adhesion molecule (sVCAM)-1, and erythrocyte sedimentation rate [ESR]). This represents the most ambitious attempt, to date, to evaluate the clinical efficacy and safety of curcumin as an anti-inflammatory agent. Significant improvements of both the clinical and biochemical end points were observed for Meriva compared to the control group. This, coupled with an excellent tolerability, suggests that Meriva is worth considering for the long-term complementary management of osteoarthritis.
Many lines of evidence now support the hypothesis that inflammation-related pathways are involved in the pathophysiology of psychiatric disorders. Much of the data underpinning this hypothesis has come from the study of inflammation-related proteins in blood of individuals with mood disorders and schizophrenia. Significantly, recent data have emerged to suggest that changes in inflammation-related pathways are present in the CNS of subjects with psychiatric disorders. It is therefore timely to overview how such data, plus data on the role of inflammation-related proteins in CNS function, is contributing to understanding the pathophysiology of mood disorders and schizophrenia. In addition, it has been suggested that antidepressants, mood stabilizers and antipsychotic drugs act on inflammation-related pathways and therefore measuring levels of inflammation-related proteins in blood may be useful in monitoring treatment responsiveness. Despite these important neuropsychopharmacological discoveries, there is no clear understanding as to how inflammatory-related pathways can precipitate the onset of psychiatric symptoms. This review will focus on data suggesting that acute-reactive proteins and cytokines are affected by the pathophysiology of mood disorders and schizophrenia, that levels of blood inflammation-related proteins before and after treatment might be useful in the diagnosis of psychiatric disorders or measuring responsiveness to drug treatment. Finally, it will be postulated how changes in these proteins affect CNS function to cause psychiatric disorders.
Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here.
Curcumin, the active component of curcuma longa, has been reported to be effective in alleviating chronic stress-induced disorders in rodents by modulating neuroprotection and neuroendocrine functions of the central nervous system, especially hippocampus. However, it is unclear whether curcumin can attenuate the subacute stress response induced by 2 h of road transport in the pig. Therefore, the present study was designed to identify the changes of serum cortisol concentration, hippocampal nitric oxide (NO) production, and related gene expression in response to 2 h of transport and to explore whether curcumin treatment (8 mg/kg, p.o.) for 21 d before transport may alleviate the stress-induced responses in the hippocampus of pigs. We found that 2 h of transport elevated serum cortisol concentration (P < 0.01), increased hippocampal NO content, and reduced brain-derived neurotrophic factor (BDNF) mRNA expression in pigs not treated with curcumin, whereas these stress responses were all reversed or attenuated in curcumin-treated pigs. In addition, the stress-induced increase in the expression of constitutive nitric oxide synthase (cNOS) and enzyme activities of total NOS, cNOS, and inducible NOS (iNOS) was also reversed or attenuated in curcumin-treated pigs. However, neither transport nor curcumin caused significant alterations in hippocampal expression of 11β-hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 2), glucocorticoid and mineralocorticoid receptors (GR and MR), or pro-/anti-apoptotic molecules (Bax-α and Bcl-xL). These results suggest that curcumin can alleviate subacute stress response in pigs through its neuroprotective effects on modulating hippocampal NO production and BDNF expression.
Bipolar disorder follows a staged trajectory in which persistence of illness is associated with a number of clinical features such as progressive shortening of the inter-episode interval and decreased probability of treatment response. This neuroprogressive clinical process is reflected by both progressive neuroanatomical changes and evidence of cognitive decline. The biochemical foundation of this process appears to incorporate changes in inflammatory cytokines, cortisone, neurotrophins and oxidative stress. There is a growing body of evidence to suggest that these markers may differ between the early and late stages of the disorder. The presence of a series of tangible targets raises the spectre of development of rational neuroprotective strategies, involving judicious use of current therapies and novel agents. Most of the currently used mood stabilisers share effects on oxidative stress and neurotrophins, while novel potentially neuroprotective agents are being developed. These developments need to be combined with service initiatives to maximise the opportunities for early diagnosis and intervention.
Overweight and obesity are highly prevalent in patients with bipolar disorder, and metabolic disorders also affect a significant portion of this population. Obesity and metabolic disorders cause significant economic burden and impair quality of life in both the general population and patients with bipolar disorder. This review examines the relationship between bipolar disorder and the metabolic syndrome, and the associated economic impact. The metabolic syndrome and bipolar disorder appear to share common risk factors, including endocrine disturbances, dysregulation of the sympathetic nervous system, and behaviour patterns, such as physical inactivity and overeating. In addition, many of the commonly used pharmacological treatments for bipolar disorder may intensify the medical burden in bipolar patients by causing weight gain and metabolic disturbances, including alterations in lipid and glucose metabolism, which can result in an increased risk for diabetes mellitus, hypertension, dyslipidaemia, cardiovascular disease and the metabolic syndrome. These medical co-morbidities and obesity have been associated with a worse disease course and likely contribute to the premature mortality observed in bipolar patients. Weight gain is also a major cause of treatment noncompliance, increased use of outpatient and inpatient services and, consequently, higher healthcare costs. Prevention of weight gain and metabolic disturbances or early intervention when these are present in bipolar disorder could result in significant health and economic benefits.
Background: This article is a critical review of the efficacy of selected alternative treatments for unipolar depression including exercise, stress management techniques, acupuncture, St. John's wort, bright light, and sleep deprivation. Issues related to women across the life span, including pregnancy and lactation, are highlighted.
Data Sources: Evidence of efficacy is based on randomized controlled trials. A distinction is made between studies that address depressive symptoms and studies that address depressive disorders. The review emphasizes issues related to effectiveness, such as treatment availability, acceptability, safety, and cost and issues relevant to women.
Data Synthesis: Exercise, stress reduction methods, bright light exposure, and sleep deprivation hold greater promise as adjuncts to conventional treatment than as monotherapies for major depression. The evidence to date is not sufficiently compelling to suggest the use of St. John's wort in favor of or as an alternative to existing U.S. Food and Drug Administration-regulated compounds. Initial evidence suggests that acupuncture might be an effective alternative monotherapy for major depression, single episode.
Conclusion: This review indicates that some unconventional treatments hold promise as alternative or complementary treatments for unipolar depression in women and have the potential to contribute to its long-term management. Additional research is needed before further recommendations can be made, and there is an urgent need to carefully document and report the frequency of minor and major side effects.
Necroptosis was reported as one backup way of programmed cell death when apoptosis was blocked, and the receptor interacting protein 1 was considered as the key necroptosis regulator protein. Here, we report the neuroprotective effects of curcumin which attenuates necroptosis. Primary cortical neurons were cultured and were injured by ferrous chloride, z.vad.fmk was applied to block apoptosis, curcumin was administrated to protect neurons, necrostatin-1 was applied to inhibit necroptosis if needed. Cell viability was measured by detecting lactate dehydrogenase activity in lysates of surviving cells, and assessed by cell counting kit-8. The expression of receptor interacting protein 1 was detected by immunoblot and immunofluorescence. Results showed that necroptosis mainly occurred in the concentrations of ferrous chloride ranging from 100μM to 200μM, curcumin attenuated necroptosis in a dose-dependent manner. Furthermore, curcumin decreased expression of receptor interacting protein 1 in a dose- and time-dependent manner. Taken together, these findings suggest that curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis.
There is now strong evidence of progressive neuropathological processes in bipolar disorder (BD). On this basis, the current understanding of the neurobiology of BD has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of BD. These features include progressive shortening of the inter-episode interval with each recurrence, occurring in consort with reduced probability of treatment response as the illness progresses. To this end, emerging data shows that these biomarkers may differ between early and late stages of BD in parallel with stage-related structural and neurocognitive alterations. This understanding facilitates identification of rational therapeutic targets, and the development of novel treatment classes. Additionally, these pathways provide a cogent explanation for the efficacy of seemingly diverse therapies used in BD, that appear to share common effects on oxidative, inflammatory and neurotrophic pathways.Research highlights▶ Bipolar disorder is associated with an active process of neuroprogression. ▶ Oxidative, inflammatory and neurotrophic factors play a role in the process. ▶ Both available treatments and novel options impact these pathways.
Both (Li+) and valproic acid (VPA) are effective in treating bipolar disorder, but the pathway by which either works, and whether it is common to both drugs, is not agreed upon. We recently reported, using an in vivo fatty acid model, that Li+ reduces the turnover rate of the second messenger arachidonic acid (AA) by 80% in brain phospholipids of the awake rat, without changing turnover rates of docosahexaenoic or palmitic acid. Reduced AA turnover was accompanied by down-regulation of gene expression and protein levels of an AA-specific cytosolic phospholipase A2 (cPLA2). To see if VPA had the same effect on AA turnover, we used our in vivo fatty acid model in rats chronically administered VPA (200 mg/kg, i.p. for 30 days). Like Li+, VPA treatment significantly decreased AA turnover within brain phospholipids (by 28–33%), although it had no effect on cPLA2 protein levels. Thus, both mood stabilizers, Li+ and VPA have a common action in reducing AA turnover in brain phospholipids, albeit by different mechanisms.
Acute treatment with valproate and Li+ was found to protect cultured cerebellar granule cells against apoptosis induced by low K+ (5 mm). Because the protection was unaffected by MK801 (N-methyl-d-aspartate receptor inhibitor), an increase in glutamate release cannot be responsible for the observed neuroprotection. Insulin also protects against low-K+-induced apoptosis of cerebellar granule cells. This protection is totally dependent on LY294002 (a phosphatidylinositol 3-kinase inhibitor). These results suggest a role for phosphatidylinositol 3-kinase in the neuroprotection induced by insulin. Likewise, and in contrast with the results observed with Li+, the protection induced by valproate is also dependent on insulin and LY294002. Moreover, valproate (a branched-chain fatty acid) does not change the plasma membrane microviscosity under physiological conditions. These results suggest that valproate protects against low-K+-induced apoptosis by acting in the phosphatidylinositol 3-kinase/protein kinase B pathway. The protection by Li+ is independent of this transduction pathway.
Phosphorylase kinase (PhK), also known as adenosine triphosphate (ATP)-phosphorylase b phosphotransferase, integrates multiple calcium/calmodulin-dependent signalling pathways, including those involved in cell migration and cell proliferation, while coupling these pathways to glycogenolysis and ATP-dependent phosphorylation, thus ensuring continuing energy supply for these activities.
Our laboratory recently reported correlation of elevated PhK activity with psoriatic activity. This study further evaluates the significance of drug-induced suppression of PhK activity on psoriatic activity.
PhK activity was assayed in four groups, each with 10 patients: (i) active untreated psoriasis; (ii) resolving psoriasis treated by calcipotriol (Dovonex(R), Bristol Myers Squibb, Princeton, NJ, U.S.A. ), a vitamin D3 analogue and an indirect inhibitor of PhK; (iii) curcumin (diferuloylmethane), a selective PhK inhibitor; and (iv) 10 normal non-psoriatic subjects.
PhK activity in units mg-1 protein was highest in active untreated psoriasis (1204 +/- 804.3; mean +/- SD), lower in the calcipotriol-treated group (550.7 +/- 192. 9), lower in curcumin-treated group (207.2 +/- 97.6), and lowest in normal skin (105.4 +/- 44.6). One-way analysis of variance performed on log-transformed PhK activity measure showed significant differences among the four groups, F3,36 = 48.79, P < 0.0001. Decreased PhK activity in curcumin-and calcipotriol-treated psoriasis was associated with corresponding decreases in keratinocyte transferrin receptor (TRR) expression, severity of parakeratosis and density of epidermal CD8+ T cells.
Our results demonstrate that drug-induced suppression of PhK activity is associated with resolution of psoriatic activity as assessed by clinical, histological and immunohistochemical criteria, and support the hypothesis that effective antipsoriatic activity may be achieved through modulation of PhK activity.
Only two-thirds of depressive patients respond to antidepressant treatment. Recently, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we examined the effects of various atypical antipsychotic drugs as adjuvant to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants and mood stabilizers, on plasma BDNF levels in refractory depressed patients. Forty-five patients who met the DSM-IV criteria for major depressive disorder (n = 31) or bipolar disorder (10 with bipolar I, 4 with bipolar II) were enrolled in the study. Twenty-one were male and 24 were female, and their ages ranged from 28 to 71 (mean ± SD = 49 ± 12) years. Plasma BDNF levels were measured using a sandwich ELISA. The plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more) were significantly increased 4 weeks after the administration of each atypical antipsychotic drug, while the levels in non-responders were not changed. Furthermore, there was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels. These results suggest that adding an atypical antipsychotic drug to ongoing treatment with an antidepressant or mood stabilizer is useful and well-tolerated for refractory depressed patients, and the efficacy of atypical antipsychotics as an adjuvant might involve an increase of plasma BDNF levels.
Curcumin is the active principle of Curcuma longa, one of the widely used components in the traditional system of medicine in India. Despite its efficacy in experimental studies aiming at neuronal disorders like depression, curcu-min's poor water solubility challenges the production of therapeutic formulations. This study investigates the antidepressant-like activity of novel water-soluble curcumin formulations, dispensed in three different concentrations. Further, the study comparatively evaluates St. John's wort (SJW), another herbal preparation.
These compounds were evaluated in the forced swimming test in mice, and the corresponding changes in the neurotransmitter levels were measured.
Three water-soluble curcumin formulations, C-5, C-20 and C-50 (50-200 mg/kg p.o.) decreased the immobility period, and increased serotonin and dopamine levels in the brain tissues. A subeffective dose (50 mg/kg) of these formulations enhanced the antidepressant-like effect of classical antidepressants with varied mechanisms of action. In addition, an SJW dose of 25 mg/kg showed a significant antidepressant-like effect in all the behavioral studies and also significantly increased brain neurotransmitter levels, especially that of serotonin. The effects produced by C-5 were comparable with those of SJW and fluoxetine, respectively.
In all these observations, the water-soluble formulations showed a significant antidepressant-like effect, including enhancement of neurotransmitter levels as compared to the similar dose of a conventional curcumin preparation. Thus, these formulations may be used as a novel treatment option in the management of mental depression.
One goal of the Canadian Network for Mood and Anxiety Treatments (CANMAT) is to develop evidence-based and best practice educational programs and recommendations. Our group conducted a comprehensive literature review to provide evidence-based recommendations for treating metabolic comorbidity in individuals with major depressive disorder (MDD) and bipolar disorder (BD).
We searched PubMed for all English-language articles published January 1966 to November 2010 using BD and MDD cross-referenced with metabolic syndrome, obesity, diabetes mellitus, hypertension, and dyslipidemia. That search was augmented by a review of articles reporting outcomes of an intervention targeting components of metabolic syndrome in individuals with MDD or BD.
Consensus exists for the recommendation that individuals with MDD and BD should be routinely screened for risk factors that increase risk for metabolic syndrome. For excess weight, the best-studied pharmacologic approaches are metformin and topiramate, with emerging evidence for liraglutide and modafinil. For binge eating disorder, the best evidence in mood disorders was for cognitive-behavioral therapy as well as topiramate, zonisamide, and in select cases selective serotonin reuptake inhibitors. For dysglycemia, dyslipidemia, and hypertension, evidence supports cognitive-behavioral interventions and anti-diabetic, antilipidemic, and antihypertensive treatments.
Comprehensive care of individuals with mood disorders should include routine evaluation of the risk and presence of metabolic syndrome and its components. Systematic evaluation of preventative and targeted treatments of metabolic syndrome in mood disorder populations is insufficient.
Painful peripheral neuropathy induced by chronic ethanol consumption is a major medico-socioeconomical problem. The objective of present investigation was to study the effect of curcumin (20, 40 and 80mg/kg; p.o.) in alcohol-induced neuropathy in rats. Ethanol (35% v/v, 10g/kg; p.o.) was administered for 10 weeks which showed a significant decrease in thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia and nerve conduction velocity. It caused enhanced malondialdehyde, oxidative-nitrosative stress, total calcium levels, inflammatory mediators (TNF-α and IL-1β levels) along with DNA damage. Co-administration of curcumin and α-tocopherol for 10 weeks significantly and dose-dependently improved nerve functions, biochemical as well as molecular parameters and DNA damage in sciatic nerve of ethanol treated rats. Hence, it was concluded that curcumin is of potent therapeutic value in the amelioration of alcoholic neuropathy in rats and acts by inhibition of pro-inflammatory mediators like TNF-α and IL-1β.
The brain and body need to adapt constantly to changing social and physical environments. A key mechanism for this adaptation is the 'stress response', which is necessary and not negative in and of itself. The term 'stress', however, is ambiguous and has acquired negative connotations. We argue that the concept of allostasis can be used instead to describe the mechanisms employed to achieve stability of homeostatic systems through active intervention (adaptive plasticity). In the context of allostasis, resilience denotes the ability of an organism to respond to stressors in the environment by means of the appropriate engagement and efficient termination of allostatic responses. In this review, we discuss the neurobiological and organismal factors that modulate resilience, such as growth factors, chaperone molecules and circadian rhythms, and highlight its consequences for cognition and behavior.
Defining refractoriness in bipolar disorder is complex and should concern and include either every phase and pole or the disorder as a whole. The data on the treatment of refractory bipolar patients are sparse. Combination and add-on studies suggest that in acutely manic patients partial responders to lithium, valproate, or carbamazepine, a good strategy would be to add haloperidol, risperidone, olanzapine, quetiapine, or aripiprazole. Adding oxcarbazepine to lithium is also a choice. There are no reliable data concerning the treatment of refractory bipolar depressives and also there is no compelling data for the maintenance treatment of refractory patients. It seems that patients stabilized on combination treatment might do worse if shifted from combination. Conclusively there are only limited and sometimes confusing data on the treatment of refractory bipolar patients. Further focused research is necessary on this group of patients.
An escalating "epidemic" of diseases like Alzheimer's has not yet been met by effective symptomatic treatments or preventative strategies. Among a few current prescription drugs are cholinesterase inhibitors including galantamine, originating from the snowdrop. Research into ethnobotanicals for memory or cognition has burgeoned in recent years. Based on a multi-faceted review of medicinal plants or phytochemicals, including traditional uses, relevant bioactivities, psychological and clinical evidence on efficacy and safety, this overview focuses on those for which there is promising clinical trial evidence in people with dementia, together with at least one other of these lines of supporting evidence. With respect to cognitive function, such plants reviewed include sage, Ginkgo biloba, and complex mixtures of other traditional remedies. Behavioral and psychological symptoms of dementia (BPSD) challenge carers and lead to institutionalization. Symptoms can be alleviated by some plant species (e.g., lemon balm and lavender alleviate agitation in people with dementia; St John's wort treats depression in the normal population). The ultimate goal of disease prevention is considered from the perspective of limited epidemiological and clinical trial evidence to date. The potential value of numerous plant extracts or chemicals (e.g., curcumin) with neuroprotective but as yet no clinical data are reviewed. Given intense clinical need and carer concerns, which lead to exploration of such alternatives as herbal medicines, the following research priorities are indicated: investigating botanical agents which enhance cognition in populations with mild memory impairment or at earliest disease stages, and those for BPSD in people with dementia at more advanced stages; establishing an ongoing authoritative database on herbal medicine for dementia; and further epidemiological and follow up studies of promising phytopharmaceuticals or related nutraceuticals for disease prevention.
Studies using augmentation of pharmacotherapies with nutraceuticals in bipolar disorder (BD) have been conducted and preliminary evidence in many cases appears positive. To date, however, no specialized systematic review of this area has been conducted. We present the first systematic review of clinical trials using nutrient-based nutraceuticals in combination with standard pharmacotherapies to treat BD. A subsequent aim of this report was to discuss posited underlying mechanisms of action.
PubMed, CINAHL, Web of Science, and Cochrane Library databases, and grey literature were searched during mid-2010 for human clinical trials in English using nutraceuticals such as omega-3, N-acetyl cysteine (NAC), inositol, and vitamins and minerals, in combination with pharmacotherapies to treat bipolar mania and bipolar depression. A review of the results including an effect size analysis (Cohen's d) was subsequently conducted.
In treating bipolar depression, positive evidence with large effect sizes were found for NAC (d=1.04) and a chelated mineral and vitamin formula (d=1.70). On the outcome of bipolar mania, several nutraceuticals reduced mania with strong clinical effects: a chelated mineral formula (d=0.83), L-tryptophan (d=1.47), magnesium (d=1.44), folic acid (d=0.40), and branched-chain amino acids (d=1.60). Mixed, but mainly positive, evidence was found for omega-3 for bipolar depression, while no evidentiary support was found for use in mania. No significant effect on BD outcome scales was found for inositol (possibly due to small samples).
BD treatment outcomes may potentially be improved by additional use of certain nutraceuticals with conventional pharmacotherapies. However, caution should be extended in interpreting the large effects of several isolated studies, as they have not yet been replicated in larger trials.
Neurotransmitters link the nervous system to immune responses associated with inflammation and poststroke infections.
Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.
To evaluate the use of curcumin in inflammatory bowel disease.
ALTMEDEX, Comprehensive Database of Natural Medicines, MEDLINE/PubMed were searched from January 1980 through May 2009 using the terms curcumin, turmeric, ulcerative colitis, Crohn's disease, Curcuma longa, Curcuma domestica, Indian saffron, inflammatory bowel disease. Data was limited to human trials. References of identified articles were reviewed.
Data evaluating the use of curcumin in inflammatory bowel disease (including ulcerative colitis and Crohn's disease) is limited to two studies comprising data for only 99 patients. Curcumin in conjunction with mainstream therapy, consisting of sulfasalazine (SZ) or mesalamine (5-aminosalicylic acid [5-ASA] derivatives) or corticosteroids was shown to improve patient symptoms and allow for a decrease in the dosage of corticosteroids or 5-ASA derivatives. In one small study of 10 patients, some patients even stopped taking corticosteroids or 5-ASA.
Although two small studies have shown promising results, all authors conclude that larger-scale, double-blind trials need to be conducted to establish a role for curcumin in the treatment of ulcerative colitis. In addition to improving results when used in conjunction with conventional medications for UC, curcumin may pose a less-expensive alternative.
Davallialactone, hispidin analogues derived from the mushroom Inonotus xeranticus, has antioxidant properties. This study examined whether the reactive oxygen species (ROS) removal activity of davallialactone affects the lipopolysaccharide (LPS)-induced anti-inflammatory activity in human dental pulp cells.
The LPS-induced formation of ROS was analyzed by using dichlorofluorescein diacetate with fluorescence-activated cell sorter, and the expression of inflammatory molecules in primary cultured human dental pulp cells was determined by immunoblotting. The inflammatory mechanism of the davallialactone-involved signal pathway was examined by immunoblotting.
Davallialactone acted as an antioxidant to confirm the elimination of ROS formation and elevation of Cu/Zn superoxide dismutase and Mn superoxide dismutase expression in LPS-induced pulp cells. The antioxidant activity of davallialactone leads to inhibition of LPS-induced inflammation by blocking the extracellular signal-regulated kinase (ERK1/2) and nuclear factor kappa B (NF-κB) pathway, which decreases the expression of inflammatory molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, matrix metalloproteinase-2, matrix metalloproteinase-9, inducible nitric oxide synthase, and cyclooxygenase-2. The character of davallialactone was more effective in comparison with N-acetylcysteine as the control antioxidant in this study.
Davallialactone has antioxidant activity and anti-inflammatory effects in LPS-induced human dental pulp cells through the suppression of ERK1/2 activation followed by blockage of NF-κB translocation from cytosol into nuclear. Therefore, the good anti-inflammatory capacity of davallialactone might be used for oral diseases such as pulpitis and periodontitis.
Yes, but data aren't plentiful. Limited evidence suggests that turmeric and its active compound, curcumin, are effective for rheumatoid arthritis and other inflammatory conditions (strength of recommendation [SOR]: C, primarily low-quality cohort studies with small patient numbers). Curcumin has shown limited benefit for patients with psoriasis, inflammatory bowel disease (IBS), inflammatory eye diseases, familial adenomatous polyposis, and kidney transplantation (SOR: B, small, short randomized controlled trials [RCTs]). No evidence indicates that curcumin helps patients with human immunodeficiency virus (HIV) (SOR: B, single RCT).
Several studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9±127.1pg/mL) compared to pre-treatment (406.3±69.5pg/mL) (p=0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithium's direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD.
A rat model of depression has been recently developed using exogenous corticosterone (CORT) administration. This study aimed to examine the antidepressant-like effect and the possible mechanisms of curcumin in a CORT-induced depression model in rats. The results showed that 3-week CORT injections caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Repeated CORT injections also significantly decreased brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex of the rats. Treatment of the rats with curcumin significantly suppressed the depression-like behavior and the decrease in brain BDNF levels induced by the repeated CORT injections. The results suggest that curcumin produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex.
Cancer is one of the leading causes of death in the United States and around the world. Most modern drug-targeted therapies, besides being enormously expensive, are associated with serious side effects and morbidity. Still, the search continues for an ideal treatment that has minimal side effects and is cost-effective. Indeed, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to prevent and treat cancer. We present evidence on numerous dietary agents identified from fruits and vegetables that act on multiple signal transduction and apoptotic cascades in various tumor cells and animal models. Some of the most interesting and well documented are turmeric (curcumin), resveratrol, silymarin, EGCG, and genistein. This review will provide an insight on the cellular and molecular mechanism(s) by which dietary agents modulate multiple signaling and apoptotic pathways in tumor cells and elucidate the role of these agents in both prevention and treatment of cancer.
Curcumin (Curcuma Longa Linn), the active component of turmeric, has been shown to be effective in ameliorating several stress and drug-induced disorders in rats and humans. However, it is unclear whether short term curcumin administration can prevent the abnormal oro-facial movements (AOFM) which develop following blockade of dopamine D2 receptors by antagonist such as Haloperidol. The objective of this study is to determine whether short term treatment with curcumin along with Haloperidol can prevent the development of AOFM in rats. Male Sprague Dawley rats were administered curcumin at 200 mg/kg, and Haloperidol at 2 mg/kg daily for 2 weeks, and AOFMs and locomotor activity were assessed at baseline, day 7 and day 14. By day 14, rats receiving concurrent curcumin administration had a significant reduction in the incidence of Haloperidol-induced AOFMs, but no change on the Haloperidol-induced hypolocomotion. There was no spiked increase in locomotor activity in absence of challenge with dopamine D2 receptor agonist. The exact mechanism by which curcumin attenuates AOFMs remains unknown, therefore, we performed a proteomic analysis of the striatal samples obtained from control and curcumin treated groups. A number of proteins were altered by curcumin, among them an antiapoptotic protein, Bcl-XL, was significantly upregulated. These results suggest that curcumin may be a promising treatment to prevent the development of AOFMs and further suggest some therapeutic value in the treatment of movement disorders.
Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation (LTP) and neurogenesis. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells (particularly T cells and macrophages), neurons, and neural precursor cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters (e.g., glutamate and monoamines) and hormones (e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFα, as well as other mediators, such as prostaglandins and neurotrophins. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation-induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity-related molecules, facilitating many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases.
Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.
Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), are the most prevalent psychiatric conditions, and are also among the most severe and debilitating. However, the precise neurobiology underlying these disorders is currently unknown. One way to combat these disorders is to discover novel biomarkers for them. The development of such biomarkers will aid both in the diagnosis of mood disorders and in the development of effective psychiatric medications to treat them. A number of preclinical studies have suggested that the brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of MDD. In 2003, we reported that serum levels of BDNF in antidepressant-naive patients with MDD were significantly lower than those of patients medicated with antidepressants and normal controls, and that serum BDNF levels were negatively correlated with the severity of depression. Additionally, we found that decreased serum levels of BDNF in antidepressant-naive patients recovered to normal levels associated with the recovery of depression after treatment with antidepressant medication. This review article will provide an historical overview of the role played by BDNF in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Particular focus will be given to the potential use of BDNF as a biomarker for mood disorders. BDNF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. Finally, future perspectives on the use of proBDNF as a novel biomarker for mood disorders will be discussed.
Bipolar disorder shares depressive symptoms with unipolar major depressive disorder but is defined by episodes of mania or hypomania. Bipolar disorder in its broadest sense has a community lifetime prevalence of 4% and is a severely impairing illness that impacts several aspects of patients' lives. Race, ethnicity, and gender have no effect on prevalence rates, but women are more likely to experience rapid cycling, mixed states, depressive episodes, and bipolar II disorder than men. Patients with bipolar disorder have high rates of disability and higher rates of mortality than individuals without bipolar disorder. Natural causes such as cardiovascular disease and diabetes, as well as suicide and other "unnatural" causes are key contributors to the high mortality rate. The costs associated with bipolar disorder include not only the direct costs of treatment, but also the much greater indirect costs of decreased productivity, excess unemployment, and excess mortality.
Introduction:
The ubiquity and hazards posed by abnormal body composition and metabolic parameters in the bipolar population are a priority research and clinical issue. Herein, we summarize and synthesize international studies describing the rate of US National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III])- and International Diabetes Federation (IDF)-defined metabolic syndrome and its criterion components in individuals with bipolar disorder.
Methods:
We conducted a PubMed search of all English-language articles published between January 2005 and July 2009 with the following search terms: metabolic syndrome and bipolar disorder, mania and manic-depression. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality.
Results:
The rate of metabolic syndrome in individuals with bipolar disorder is increased relative to the general population. Disparate estimates are reported ranging from comparability to approximately twofold greater than the general population. The increased hazard for metabolic syndrome amongst bipolar individuals is now documented in twelve countries from Europe, Australia, Asia, North and South America. The co-occurrence of metabolic syndrome in the bipolar population is associated with a more complex illness presentation, less favourable response to treatment, and adverse course and outcome. The association between metabolic syndrome and bipolar disorder is mediated/moderated by both iatrogenic and non-iatrogenic factors.
Discussion:
The increased hazard for metabolic syndrome in bipolar populations is due to the clustering of traditional (and emerging) risk factors as well as iatrogenic and health systems factors. Extant data support recommendations for prioritizing, surveillance, prevention, diagnosis and management of metabolic syndrome as routine care of the bipolar patient.
Recent evidence suggests that peripheral markers related to oxidative stress, inflammation and neurotrophins may be altered during mood episodes in bipolar disorder. These can be seen as proxies of peripheral toxicity or markers of illness activity. Here we report an en bloc assessment of a set of previously described biomarkers in different mood states (n = 60) as well as in healthy subjects (n = 80). To make the point that these are ominous changes, we obtained the same measures from a group of septic patients (n = 15) as a "positive" control group. In this sample, we measured serum levels of brain derived neurotrophic factor, neurotrophin 3, tumor necrosis factor α, interleukin 6, interleukin 10, total reactive antioxidant potential, thiobarbituric acid reactive substances and protein carbonyl content. Several of the markers discriminated between the bipolar and control groups, especially when patients were in acute episodes. In some cases, toxicity was as high in bipolar disorder as that seen in patients with sepsis. We believe these findings highlight the potential of using biomarkers to assess illness activity in bipolar disorder.
The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders.