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The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A randomized controlled study



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Letter to the Editor
The effects of curcumin on brain-derived
neurotrophic factor and cognition in
schizophrenia: A randomized
controlled study
Curcumin is a polyphenolic compound derived from the spice tur-
meric (Curcuma longa) with potential as a complementary treatment
for people with schizophrenia. In preclinical studies, curcumin has
been reported to have anti-oxidant, anti-inammatory, neuroprotec-
tive, and pro-cognitive properties, as well as increased levels of brain-
derived neurotrophic factor (BDNF) (Dong et al., 2012; Fanaei et al.,
2016; Motaghinejad et al., 2017). The effects of curcumin on BDNF
and neurocognition are particularly relevant for schizophrenia as well-
documented lower levels of BDNF and neurocognitive decits have
been reported (Green et al., 2011).
We examined the effects of curcumin in patients with schizophrenia
in an 8-week randomized, double-blind, placebo-controlled study,
assessing BDNF levels, clinical symptoms, and measures of social and
non-social cognition. We hypothesized that curcumin would increase
BDNF levels and improve cognitive performance.
Forty-ve stable, medicated outpatients meeting DSM-5 criteria for
schizophrenia were recruited from the VA Greater Los Angeles
Healthcare System (VAGLAHS) and outpatientclinics in the Los Angeles
area. All participants had the capacity to give and provided written in-
formed consent in accordance with procedures approved by the Institu-
tional Review Board at VAGLAHS. This study was registered with (identier: NCT02104752).
Curcumin capsules and matched placebo were provided by
Theravalues Corporation (Tokyo, Japan). Subjects randomized to
curcumin received 360 mg/day (divided into twice daily oral doses);
those randomized to placebo receivedan equal number of capsules. Par-
ticipants received clinical and cognitive assessments as well as blood
draws at baseline (prior to study treatment), and at 4- and 8-weeks
post baseline.
Serum BDNF levels were analyzed by the UCLA Immunogenetics
Center/UCLA Immune Assessment Core. Analysis was performed on
human serum samples with the Human BDNF Quantikine ELISA (R&D
Systems, Minneapolis, MN). Results are reported in pg/mL.
The MATRICS Consensus Cognitive Battery (MCCB) was used to as-
sess non-social cognition. Age and gender-corrected normed T-scores
for the global composite were analyzed. The Empathic Accuracy task
(Kern et al., 2013) was used to assess social cognition. For symptom as-
sessments, we used the Brief Psychiatric Rating Scale and the Clinical
Assessment Interview for Negative Symptoms.
For analyses, we used a generalized linear mixed model, which in-
cluded xed effects for time, treatment and treatment-by-time interac-
tions, and a random intercept term for each participant. The primary
effect of interest was the treatment-by-time interaction as it models dif-
ferences in change over time that can be attributed to treatment.
Thirty-six patients (curcumin n = 17, placebo n = 19) had useable
data. For BDNF, there were no signicant main effects of treatment
or time. However, the treatment × time interaction was signicant,
= 4.23, p = 0.043. Patients receiving curcumin showed increased
levels of BDNF relative to baseline, whereas patients receiving placebo
showed declines relative to baseline (Fig. 1). There were no signicant
differences in BDNF levels between the curcumin and placebo groups
at baseline. The treatment × time interactions for symptoms and cogni-
tion were not signicant.
This is the rst study evaluating the effects of curcumin on BDNF, and
clinical and cognitive measures in patients with schizophrenia. In this
study, curcumin increased BDNF levels over the treatment period, com-
pared to placebo. These results demonstrate that curcumin may have a re-
liable biomarker in its effects on BDNF, but did not show more distal
effects on cognition or clinical symptoms for patients with schizophrenia.
While the exact mechanism through which curcumin can increase BDNF
levels is unknown, it may work through enhanced expression of the BDNF
gene via phosphorylated cAMP response element-binding protein (CREB)
(Xu et al., 2006). As alterations in CREB have been noted in people with
schizophrenia (Ren et al., 2014), curcumin could potentially reverse
these decits, thereby leading to increased expression of BDNF.
A major limitation in clinical trials of curcumin has been poor ab-
sorption and bioavailability of earlier preparations of curcumin (Gupta
et al., 2013), as well as rapid metabolism by the liver and intestine.
We used a formulation of curcumin nanoparticles (Theracurmin)
which is highly bioavailable and well-tolerated in humans (Sasaki et
al., 2011). As this was a preliminary study with a modest sample size,
we did not have sufcient power to detect small differences in cognition
and symptoms. The results of the current study should be interpreted
with caution until replication with larger sample sizes.
These results are promising regarding a proximal biomarker, BDNF,
and may have long-term benets for cognition and symptoms that
would not be observable in an 8-week trial. Because the development of
schizophrenia has been linked to increased inammatory response, oxi-
dative stress, and abnormal neural pruning (Barron et al., 2017), a thera-
peutic agent that alleviates one or more of these by increasing BDNF could
protect processes (e.g., poor learning, memory, neuroplasticity) impacted
by the disease.
Conict of interest
In the past3 years, MFG has received researchsupport from Forum, has been a consul-
tant for AbbVie, ACADIA, DSP, and Takeda; and is on the scientic board of Luc. SRM has
received research support from Neurocrine and Fo rum and has been a consultant for
Allergan, Teva, Takeda, Roche, Lundbeck, Jazz, and Forum. The remaining authors report
no conict of interest.
Schizophrenia Research xxx (2017) xxxxxx
SCHRES-07560; No of Pages 2
Clinical trial registration: Curcumin as a Novel Treatment to Improve Cognitive
Dysfunction in Schizophrenia,, identier:
0920-9964/Published by Elsevier B.V.
Contents lists available at ScienceDirect
Schizophrenia Research
journal homepage:
Please cite this article as: Wynn, J.K., et al., The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A ran-
domized controlled study, Schizophr. Res. (2017),
Drs. Wynn, Davis, and Marder designed the study. Drs. Wynn and Hellemann con-
ducted the data analyses. Miss Karunaratne collected blood samples and assisted with
BDNF and other statistical analyses. Dr. Wynn wrote the rst draft of the manuscript.
Drs. Wynn,Davis, Green, andMarder edited themanuscript and helped with the interpre-
tation of the ndings. All authors contributed to and have approved the nal manuscript.
Funding and disclosures
This work was supported by grant 13T-003 from the Stanley Medical Research Institute
(JKW and SRM, co-PIs), NIMH Grant R01 MH095878 (MFG, PI), and by a Department of Vet-
erans Affairs Research Enhancement Program (MFG, PI). Theravalues Corporation (Tokyo,
Japan) generously donated drug and matched placebo capsules. The funding agencies and
Theravalues Corporation had no further role in the design, analysis, interpretation, or deci-
sion in publication of this study. For Michael C. D avis, participation occurred prior to his cur-
rent position. The contents herein do not represent the views of the U.S. Department of
Veterans Affairs, the U.S. Food and Drug Administration, or the United States Government.
The authorswould like to thank Theravalues Corporation (Tokyo,Japan) for their gen-
erous donation of drug and matched placebo pills. The authors would also like to thank
Aaron McNair and Gabrielle Pascual for assistance with data collection and entry.
Barron, H., Hazi, S., Andreazza, A.C., Mizrahi, R., 2017. Neuroinammation and oxidati ve
stress in psychosis and psychosis risk. Int. J. Mol. Sci. 18 (3).
Curcumin enhances neurogenesis and cognition in aged rats: implications for transcrip-
tional interactions related to growth and synaptic plasticity. PLoS One 7 (2), e31211.
Fanaei, H., Khayat, S., Kasaeian, A., Javadimehr, M., 2016. Effect of curcumin on serum
brain-derived neurotrophic factor levels in women with premenstrual syndrome: a
randomized, double-blind, placebo-controlled trial. Neuropeptides 56, 2531.
Green, M.J., Matheson,S.L., Shepherd, A.,Weickert, C.S., Carr, V.J., 2011. Brain-derived neu-
rotrophicfactor levels in schizophrenia: a systematic review with meta-analysis.Mol.
Psychiatry 16, 960972.
Gupta, S.C., Patchva, S., Aggarwa l, B.B., 2013. The rapeutic roles of curc umin: lessons
learned from clinical trials. AAPS J. 15 (1), 195218.
Kern, R.S., Penn, D., Lee, J., Horan, W.P., Reise, S.P., Ochsner, K.N., Marder, S.R., Green, M.F.,
2013. Adapting social neuroscience measures for schizophrenia clinical trials, part 2:
trolling the depths of psychometric properties. Schizophr. Bull. 39, 12011210.
Motaghinejad, M., Motevalian, M., Fatima, S., Hashemi, H., Gholami, M., 2017. Curcumin
confers neuroprotection against alcohol-induced hippocampal neurodegeneration
via CREB-BDNF pathway in rats. Biomed Pharmacother 87, 721740.
Ren, X., Rizavi, H.S., Khan, M.A., Bhaumik, R., Dwivedi, Y., Pandey, G.N., 2014. Alteration of
cyclic-AMP response element binding protein in the postmortem brain of subjects
with bipolar disorder and schizophrenia. J. Affect. Disord. 152-154, 326333.
Sasaki, H., Sunagawa, Y., Takahashi, K., Imaizumi, A., Fukuda, H., Hashimoto, T., Wada, H.,
Katanasaka,Y.,Kakeya,H.,Fujita,M.,Hasegawa,K.,Morimoto,T.,2011.Innovative prep-
aration of curcumin for improved oral bioavailability. Biol. Pharm. Bull. 34 (5), 660665.
Xu, Y., Ku, B., Tie, L., Yao, H., Jiang, W., Ma, X., Xuejun, L., 2006. Curcumin reverses the ef-
fects of chornic stress on behavior, the HPA axis, BDNF expression and phosphoryla-
tion of CREB. Brain Res. 1122, 5664.
Jonathan K. Wynn*
Michael F. Green
Mental Illness Research, Education and Clinical Center, Veterans Affairs
Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, CA, USA
Corresponding author at: VA Greater Los Angeles Healthcare System/
UCLA, MIRECC, Bldg. 210, Rm. 115, 11301 Wilshire Blvd., Los Angeles, CA
90073, USA.
E-mail address: (J. K. Wynn).
Gerhard Hellemann
Kumari Karunaratne
Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, CA, USA
Michael C. Davis
United States Food and Drug Administration, Silver Spring, MD, USA
Stephen R. Marder
Mental Illness Research, Education and Clinical Center, Veterans Affairs
Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, CA, USA
14 June 2017
Available online xxxx
Fig. 1. Mean blood serum levels(pg/mL) at baseline(time 0) and at 4- and 8-weeks of treatmentfor schizophreniapatients on curcumin(solid line) or placebo (dashed line). There wasa
signicant interaction (p = 0.043) such that curcumin resulted in increased BDNF at 4- and 8-weeks of treatment whereas there the placebo group showed decreased BDNF over time.
2Letter to the Editor
Please cite this article as: Wynn, J.K., et al., The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: A ran-
domized controlled study, Schizophr. Res. (2017),
... Zhu et al. published a meta-analysis investigating the effect of curcumin on cognition in 2019 [12], summarizing the RCTs available between 2008 and 2018 [10,11,[13][14][15][16]. They also performed a subgroup analysis according to participants based on the presence of older age, Alzheimer's disease, and schizophrenia. ...
... One article was excluded because it was a review of an already-included RCT [25] (Table S3). Finally, eight articles were included [10,11,13,15,16,[26][27][28]. The clinical trial registry data of these eight articles were also checked and analyzed for qualitative and quantitative analyses [29][30][31][32][33][34][35]. ...
... The study duration ranged from 8 to 18 months. The enrolled subjects included older adults in four studies [11,15,27,28], patients with Alzheimer's disease in two studies [10,13], and patients with schizophrenia in two studies [16,26]. The curcumin formulations were Theracumin ® in three studies [15,16,26], Brain Active ® in one study [28], Longvida ® in one study [27], Biocurcumax ® in one study [11], Curcumin C3 Complex ® in one study [10], and powders of Kancor flavors or capsules of Arjuna Natural Extracts in one study [13]. ...
Full-text available
Curcumin is a polyphenol with strong antioxidant and anti-inflammatory effects that has been shown to be effective in ameliorating cognitive decline in animal studies. However, its clinical effectiveness is inconclusive, and relevant gastrointestinal adverse events (AEs) have been reported. The aim of this meta-analysis was to summarize the existing evidence from randomized controlled trials (RCTs) of effects of curcumin on overall cognitive function, individual cognitive domains, and gastrointestinal AE. The study includes 8 RCTs and 389 participants. A random-effects model was used for the meta-analysis. Compared with the placebo group, the curcumin group was associated with an improvement in working memory (Hedges’ g = 0.396, 95% confidence interval (CI) = 0.078 to 0.714, p = 0.015) and a borderline benefit in processing speed (Hedges’ g = 0.303, 95% CI = ‒0.013 to 0.619, p = 0.06). In the domains of language, episodic memory/visual learning, verbal memory, cognitive flexibility/problem solving, and overall cognitive function, no significant difference existed for the comparison between the curcumin and placebo groups. The curcumin group had a significantly higher risk of gastrointestinal AEs than the placebo group (odds ratio = 3.019, 95% CI = 1.118 to 8.150, p = 0.029). In the future, the effects of curcumin on working memory, processing speed, and gastrointestinal AE should be further investigated.
... Outcome of the literature Review was underpowered, with a small sample size. 48 Another pilot study examined a lower dose of add-on curcumin (180 mg/day) in chronic stable schizophrenia patients. Curcumin significantly reduced pro-inflammatory cytokine (IL-6) levels and improved working memory performance at 12 weeks. ...
... Further studies demonstrated its efficacy in reducing inflammatory markers and improving neuroplasticity markers and cognition in schizophrenia. 48,49 Importantly, two double-blind, placebo-controlled trials reported add-on curcumin's efficacy in reducing the negative symptoms of schizophrenia. 50,51 Four out of five clinical studies reviewed utilized double-blind, randomized controlled designs with active placebo arms. ...
... Nanocurcumin capsules were used in three studies. 48,49,51 One study used a combination of curcumin and piperine. 47 All the doses were tolerated well, and none of the participants withdrew from these studies owing to intolerable adverse effects. ...
Full-text available
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.
... However, to our knowledge, there are no published results to date. In 2017, the first randomized, double-blind, placebo-controlled study reporting the effects of curcumin on brain-derived neurotrophic factor (BDNF), a neurotrophin involved in neuroprotection, neuroregeneration and cell survival among other functions, and cognition in 36 patients with schizophrenia and inpatients was published [31]. Patients receiving curcumin (360 mg/day for 8 weeks) showed an increased in BDNF levels relative to baseline and compared to placebo. ...
Full-text available
Curcumin is a polyphenol extracted from the rhizome of the turmeric plant. Beyond its common use as a culinary spice in Eastern Asia, curcumin has been proposed as a therapeutic compound due to its antioxidant, anti-inflammatory and neuroprotective properties. Thus, its efficacy has been evaluated in various inflammatory-based psychiatric disorders, such as schizophrenia, depression, or autism. Our aim is to review those preclinical and clinical studies carried out in psychiatric disorders whose therapeutic approach has involved the use of curcumin and, therefore, to discern the possible positive effect of curcumin in these disorders. Preclinical studies and completed clinical trials of curcumin for psychiatric disorders published from January 2005 to October 2021 were identified through searching relevant databases until 31st October 2021. Sixty-five preclinical studies and 15 clinical trials and open-label studies were selected. Results showed a bias toward studies in depression and, to a lesser extent, schizophrenia. In all disorders, the results were positive in reducing psychiatric deficits. Despite the considerable number of beneficial outcomes reported, the small number of trials and the heterogeneity of protocols make it difficult to draw solid conclusions about the real potency of curcumin in psychiatric disorders.
... Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that plays a role in the inflammatory pathway in the central nervous system, and it is considered a candidate gene for the pathogenesis of schizophrenia [70,110]. BDNF is a member of the neurotrophic family growth factor supporting differentiation, maturation, and survival of neurons. ...
Full-text available
Schizophrenia is a neuropsychiatric disorder characterized by dissociation of thoughts, idea, identity, and emotions. It has no central pathophysiological mechanism and precise diagnostic markers. Despite its high heritability, there are also environmental factors implicated in the development of schizophrenia. Epigenetic factors are thought to mediate the effects of environmental factors in the development of the disorder. Epigenetic modifications like DNA methylation are a risk factor for schizophrenia. Targeted gene approach studies attempted to find candidate gene methylation, but the results are contradictory. Genome-wide methylation studies are insufficient in literature and the available data do not cover different populations like the African populations. The current genome-wide studies have limitations related to the sample and methods used. Studies are required to control for these limitations. Integration of DNA methylation, gene expression, and their effects are important in the understanding of the development of schizophrenia and search for biomarkers. There are currently no precise and functional biomarkers for the disorder. Several epigenetic markers have been reported to be common in functional and peripheral tissue. This makes the peripheral tissue epigenetic changes a surrogate of functional tissue, suggesting common epigenetic alteration can be used as biomarkers of schizophrenia in peripheral tissue.
... [43] Till date, few clinical studies assessed the effectiveness of add-on curcumin treatment in schizophrenic patients. [44,45] The results of our study are in-line with the findings of a recent clinical trial conducted to evaluate the effectiveness of curcumin in patients with schizophrenia as an add-on therapy. [46] Therefore, further studies with varying doses of curcumin need to be conducted to evaluate its effect on the animal models of schizophrenia. ...
Full-text available
Schizophrenia is a severe neuro-developmental psychiatric disorder. Curcumin is a polyphenolic compound extracted from turmeric. It is known for its antioxidant, anti-inflammatory, neuroprotective, and precognitive properties. The purpose of the current study was to evaluate the role of curcumin in scopolamine induced cognitive impairment in animal model of schizophrenia. The elevated plus-maze test was utilised to study the curcumin effect on learning and memory. Curcumin (100 mg/kg, i.p.) was administered daily for 28 days in animals. Behavioural tests such as transfer latency (TL) and spontaneous alteration behaviour was assessed after the last dose of curcumin on the 28th day, followed by biochemical estimations. Present study reported that curcumin showed anti-amnesic effect in animal models of cognitive impairment of schizophrenia. Curcumin reduced the TL compared to toxic control group (scopolamine per se) (P <0.001) in elevated plus maze. In spontaneous alteration behaviour test, curcumin significantly increased percentage alteration and possible alteration as compared to toxic control group (P <0.001). A significant change in acetyl cholinesterase activity, nitrate and oxidative parameters was observed, thus, confirming its anti acetyl cholinesterase, NOS (nitric oxide synthase) inhibition and antioxidant properties (P <0.05). The present study put forward the claim of curcumin as a new and safer therapeutic alternative for the treatment of cognitive impairment in Schizophrenia. The underlying mechanism of this potential effect may be related to anticholinesterase and nitric oxide synthase inhibition activity of curcumin. Further research is warranted for confirming the suggested pathways accountable for memory alleviating effects of curcumin in Schizophrenia.
... To date, only a few clinical trials or studies have evaluated nanocurcumin or encapsulated curcumin as the sole type of intervention (examples: (Belcaro et al., 2010a;NIH, 2020b;Gupte et al., 2019;Hu et al., 2018;Anselmo and Mitragotri, 2019;NIH, 2020c;Amalraj et al., 2017)). Nevertheless, curcumin nanoformulations are promising to reduce cognitive dysfunction in schizophrenia (Wynn et al., 2018), osteoarthritic pain in the knee (Gupte et al., 2019), or the symptoms of rheumatoid arthritis (Amalraj et al., 2017). ...
Aging increases the susceptibility to a diverse set of diseases and disorders, including neurodegeneration, cancer, diabetes, and arthritis. Natural compounds are currently being explored as alternative or complementary agents to treat or prevent aging-related malfunctions. Curcumin, a phytochemical isolated from the spice turmeric, has garnered great interest in recent years. With anti-oxidant, anti-inflammatory, anti-microbial, and other physiological activities, curcumin has great potential for health applications. However, the benefits of curcumin are restricted by its low bioavailability and stability in biological systems. Curcumin nanoformulations, or nano-curcumin, may overcome these limitations. This review discusses different forms of nano-curcumin that have been evaluated in vitro and in vivo to treat or prevent aging-associated health impairments. We describe current barriers for the routine use of curcumin nanoformulations in the clinic. Our review highlights outstanding questions and future work that is needed to ensure nano-curcumin is efficient and safe to lessen the burden of aging-related health problems.
... Genetic expression of BDNF may be increased via phosphorylated cAMP response element binding protein by Curcumin leading to such effect. [42] Supplementation of curcumin is also found to increase brain-derived neurotrophic factor (BDNF) levels in women having premenstrual syndrome (PMS) and decrease the symptoms of PMS. [43] Curcumin at a dose of 1000 mg/day for 6 weeks is found to decrease depressive symptoms, pro-inflammatory cytokines (IL-1β and TNF-ɑ) and salivary cortisol and increase the efficiency of antidepressant treatment in adult male patients having major depressive disorder. ...
Mental health problems and morbidities are increasing day by day. The etiology of mental health disorders is extremely complex and encompasses a range of genetic, dietary, emotional, and social as well as lifestyle factors. Finding adequate therapeutic and preventive strategies for mental health promotion is a great challenge. India is a country which is famous for its flora and fauna, many of which possess functional and medicinal properties. This article summarizes the mental health role of some selected functional foods of Indian origin, namely, brahmi (Bacopa monnieri), ashwagandha (Withania somnifera), turmeric (Curcuma longa), garlic (Allium sativum), and pumpkin seeds (Cucurbita maxima). Relevant article searches were conducted in PubMed, Google Scholar, and Google to identify the scientific articles highlighting the role of the functional foods on various mental health problems such as neurodegeneration, Alzheimer's disease, Parkinson's disease, depression, epilepsy, stress, and anxiety. The eligible articles were reviewed to gather information. These functional foods were found to be highly beneficial in treating and preventing mental health disorders mainly due to their antioxidant and anti-inflammatory properties as well as their ability to prevent mitochondrial dysfunction and degrade abnormal protein aggregates. These functional foods were also found to be effective in the improvement of the activities of various neurotransmitters such as acetylcholine and monoamines. These foods can be incorporated into the diet as well as can be used to develop drugs and nutraceuticals for treating various psychiatric problems.
... The effects of curcumin on neurocognition and BDNF is relevant for schizophrenia as well with levels of neurocognition shortage and lower level of BDNF is observed (Green, Matheson et al., 2011). Schizophrenia is linked with increased oxidative stress, abnormal neural pruning and inflammatory response (Barron, Hafizi et al. 2017), a therapeutic agent that stimulates one or more of them by increasing BDNF can protect processes like neuroplasticity, poor learning and memory influenced by the disease (Wynn, Green et al., 2018). ...
Full-text available
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.
The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.
Purpose/background: It is well documented that one of the pathophysiological mechanisms of negative symptoms in patients with schizophrenia is hypofunction of N-methyl-d-aspartate receptors. This double-blind, placebo-controlled clinical trial was designed to assess the efficacy and safety of nanocurcumin as an adjuvant agent on psychotic symptoms, especially negative symptoms, in patients with chronic schizophrenia. Methods/procedures: Fifty-six inpatients with stable chronic schizophrenia and predominant negative symptoms were randomized in a 1:1 ratio to nanocurcumin soft gel capsule (160 mg/d) and control groups, along with their antipsychotic regimen for 16 weeks. The efficacy of treatment was assessed by Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Clinical Global Impressions-Severity, and Clinical Global Impressions-Improvement scales. Extrapyramidal symptoms were evaluated by Simpson-Angus Scale and Barnes Akathisia Rating Scale. Patients were assessed at baseline and weeks 4, 8, 12, and 16 after the medication started. Findings/results: No significant differences were observed in demographic or clinical variables between both groups at baseline. The nanocurcumin group showed significantly greater improvement on the negative subscale (P = 0.05), the general psychopathology subscale (P < 0.001), the positive subscale (P = 0.004), total Positive and Negative Syndrome Scale (P < 0.001), Clinical Global Impressions-Severity (P < 0.001), and Clinical Global Impressions-Improvement scores (P < 0.001) in comparison with the control group at the endpoint. Extrapyramidal symptom rating scales and Calgary Depression Scale for Schizophrenia and frequency of other adverse effects were comparable between 2 groups. Implications/conclusions: The present study indicates nanocurcumin as a safe and potential adjunctive treatment strategy for treatment of primary negative symptoms of schizophrenia.
Full-text available
Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.
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The psychometric properties of 4 paradigms adapted from the social neuroscience literature were evaluated to determine their suitability for use in clinical trials of schizophrenia. This 2-site study (University of California, Los Angeles and University of North Carolina) included 173 clinically stable schizophrenia outpatients and 88 healthy controls. The social cognition battery was administered twice to the schizophrenia group (baseline, 4-week retest) and once to the control group. The 4 paradigms included 2 that assess perception of nonverbal social and action cues (basic biological motion and emotion in biological motion) and 2 that involve higher level inferences about self and others’ mental states (self-referential memory and empathic accuracy). Each paradigm was evaluated on (1) patient vs healthy control group differences, (2) test-retest reliability, (3) utility as a repeated measure, and (4) tolerability. Of the 4 paradigms, empathic accuracy demonstrated the strongest characteristics, including large between-group differences, adequate test-retest reliability (.72), negligible practice effects, and good tolerability ratings. The other paradigms showed weaker psychometric characteristics in their current forms. These findings highlight challenges in adapting social neuroscience paradigms for use in clinical trials.
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Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E(2), prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
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Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity.
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Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage.
Background: Alcohol abuse causes severe damage to the brain neurons. Studies have reported the neuroprotective effects of curcumin against alcohol-induced neurodegeneration. However, the precise mechanism of action remains unclear. Methods: Seventy rats were equally divided into 7 groups (10 rats per group). Group 1 received normal saline (0.7ml/rat) and group 2 received alcohol (2g/kg/day) for 21days. Groups 3, 4, 5 and 6 concurrently received alcohol (2g/kg/day) and curcumin (10, 20, 40 and 60mg/kg, respectively) for 21days. Animals in group 7 self- administered alcohol for 21days. Group 8 treated with curcumin (60mg/kg, i.p.) alone for 21days. Open Field Test (OFT) was used to investigate motor activity in rats. Hippocampal oxidative, antioxidative and inflammatory factors were evaluated. Furthermore, brain cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and brain derived neurotrophic factor (BDNF) levels were studied at gene level by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, protein expression for BDNF, CREB, phosphorylated CREB (CREB-P), Bax and Bcl-2 was determined by western blotting. Result: Voluntary and involuntary administration of alcohol altered motor activity in OFT, and curcumin treatment inhibited this alcohol-induced motor disturbance. Also, alcohol administration augmented lipid peroxidation, mitochondrial oxidized glutathione (GSSG), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and Bax levels in isolated hippocampal tissues. Furthermore, alcohol-induced significant reduction were observed in reduced form of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities and CREB, BDNF and Bcl-2 levels. Also curcumin alone did not change the behavior and biochemical and molecular parameters. Conclusion: Curcumin can act as a neuroprotective agent against neurodegenerative effects of alcohol abuse, probably via activation of CREB-BDNF signaling pathway.
Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=-0.458, 95% confidence interval=-0.770 to -0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.
Curcuma longa is a major constituent of the traditional Chinese medicine Xiaoyao-san, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and its antidepressant effects were described in our prior studies in mouse models of behavioral despair. We hypothesized that curcumin may also alleviate stress-induced depressive-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Thus in present study we assessed whether curcumin treatment (2.5, 5 and 10 mg/kg, p.o.) affects behavior in a chronic unpredictable stress model of depression in rats and examined what its molecular targets may be. We found that subjecting animals to the chronic stress protocol for 20days resulted in performance deficits in the shuttle-box task and several physiological effects, such as an abnormal adrenal gland weight to body weight (AG/B) ratio and increased thickness of the adrenal cortex as well as elevated serum corticosterone levels and reduced glucocorticoid receptor (GR) mRNA expression. These changes were reversed by chronic curcumin administration (5 or 10 mg/kg, p.o.). In addition, we also found that the chronic stress procedure induced a down-regulation of brain-derived neurotrophic factor (BDNF) protein levels and reduced the ratio of phosphorylated cAMP response element-binding protein (pCREB) to CREB levels (pCREB/CREB) in the hippocampus and frontal cortex of stressed rats. Furthermore, these stress-induced decreases in BDNF and pCREB/CREB were also blocked by chronic curcumin administration (5 or 10 mg/kg, p.o.). These results provide compelling evidence that the behavioral effects of curcumin in chronically stressed animals, and by extension humans, may be related to their modulating effects on the HPA axis and neurotrophin factor expressions.