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Kulkarni SK, Bhutani MK, Bishnoi M. Antidepressant activity of curcumin: involvement of serotonin and dopamine system. Psychopharmacology (Berl) 201: 435-442

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Abstract

Curcumin is a major active principle of Curcuma longa, one of the widely used preparations in the Indian system of medicine. It is known for its diverse biological actions. The present study was designed to investigate the involvement of monoaminergic system(s) in the antidepressant activity of curcumin and the effect of piperine, a bioavailability enhancer, on the bioavailability and biological effects of curcumin. METHODS AND OBSERVATIONS: Behavioral (forced swim test), biochemical (monoamine oxidase (MAO) enzyme inhibitory activity), and neurochemical (neurotransmitter levels estimation) tests were carried out. Curcumin (10-80 mg/kg, i.p.) dose dependently inhibited the immobility period, increased serotonin (5-hydroxytryptamine, 5-HT) as well as dopamine levels (at higher doses), and inhibited the monoamine oxidase enzymes (both MAO-A and MAO-B, higher doses) in mice. Curcumin (20 mg/kg, i.p.) enhanced the anti-immobility effect of subthreshold doses of various antidepressant drugs like fluoxetine, venlafaxine, or bupropion. However, no significant change in the anti-immobility effect of imipramine and desipramine was observed. Furthermore, combination of subthreshold dose of curcumin and various antidepressant drugs resulted in synergistic increase in serotonin (5-HT) levels as compared to their effect per se. There was no change in the norepinephrine levels. The coadministration of piperine (2.5 mg/kg, i.p.), a bioavailability enhancing agent, with curcumin (20 and 40 mg/kg, i.p.) resulted in potentiation of pharmacological, biochemical, and neurochemical activities. The study provides evidences for mechanism-based antidepressant actions of curcumin. The coadministration of curcumin along with piperine may prove to be a useful and potent natural antidepressant approach in the management of depression.

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... Curcumin is a more potent antioxidant than any other antioxidant nutrients, such as β-carotene and vitamins E and C (Suresh & Srinivasan, 2007). Chronic administration of curcumin has been reported to exert a neuroprotective-like effect in rat brain (Shrinivas, Mohit, & Mahendra, 2008). Curcumin has found with antidepressant function by assisting the role of monoaminergic systems and controlling the release of neurotransmitters, such as 5-Hydroxyindoleacetic Acid (5-HIAA), epinephrine, norepinephrine, and dopamine (Xiaolie et al., 2016). ...
... The effects of fluoride on brain neurochemistry are more pronounced in younger rats (Niu, Sun, Wang, Cheng, & Wang, 2008). Shrinivas et al., (2008) reported that curcumin restored the locomotor activities altered by environmental toxicants. Xu et al., (2005) also investigated the neuroprotective action of curcumin on altered behavioral activities in animal models. ...
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Introduction: Curcumin, a yellow-pigment, found in the popular Indian spice turmeric (Curcuma longa), poses pharmaceutical applications due to its anti-inflammatory, antioxidant, and chemoprotective properties. Excessive fluoride causes fluorosis leading to neurodegeneration and associated behavioral deficits, particularly in children. This study aimed at investigating the neuroprotective ability of curcumin on sodium fluoride (NaF)-related alterations of acetylcholine, catecholamines, histological changes in hippocampus and behavior of rats exposed to NaF during pre- and post-natal period. Methods: Pregnant albino Wistar rats were chosen and divided into four groups. The experimental period lasted 53 days (i.e. the gestational period of 23 days and post-gestational period of 30 days), at which the control group received normal tap water, the experimental group received NaF (20 ppm/kg bw) through drinking water, and the protective groups received curcumin (10 mg and 20mg/kg bw) by gavage and NaF (20 ppm/kg bw) through drinking water. Behavioral study (open field test) was done using postnatal pups aged 21 and 30 days. The brains of postnatal pups aged 1, 7, 14, 21, and 30 days were collected and used for biochemical analysis and those of pups aged 14, 21, and 30 days were used for histopathological analysis. Results: NaF-exposed rats showed a significant (p
... In addition, several models of MDD were used, most of them (21) The antidepressant efficacy of curcumin in modulating depressive behavior in different animal models has been shown in a large number of behavioral studies. Most of the studies reported improved performance in the forced swimming test [35][36][37][38][39][40][41][42][43][44][45][46][47][48], increased locomotor activity in the open field test [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64], decreased anxiety in the elevated plus maze test [57,59,[64][65][66], improved anhedonia in the sucrose preference test [51,52,54,56,58,62,[67][68][69][70][71][72][73][74][75][76], improved short and long-term memory in the passive avoidance test [49,50,55] and water maze test [54,60,77], reduced escape response in the shuttle-box test [78], attenuated the effort-related abnormalities in a choice procedure test [79], and reduced stress in the tail suspension test [50,64,66,69,[80][81][82][83][84][85][86][87][88]. Only one study found no improvements in anxiety, as measured by the open field and elevated plus maze tests, nor in "depressive-like" states, as measured by the forced swimming test [89]. ...
... Twenty studies reported an increment of 5-HT levels in the hippocampus, striatum or frontal cortex, which may be due to the interaction found between curcumin and 5-HT/cAMP/PKA/CREB/BDNF-signaling pathway or 5-HT 1A/1B and 5-HT 2C receptors [35,40,80,83,85,90]. Besides, fifteen studies reported an increased level of DA [38,41,42,[44][45][46]48,49,55,72,77,81,87,91]. NA was also incremented in five studies [46,49,55,63,86]. ...
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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.
... Phytochemicals such as phenolic acids, carotenoids, terpenoids, organosulfur compounds, and phytosterols are the antioxidant compounds of vegetables, fruits, whole grains, nuts and legumes [18]. The experimental studies have indicated the antidepressant activity of phytochemicals [19][20][21]. In addition, phytochemicals have beneficial effects on determinants of depression such as abdominal obesity, oxidative stress and inflammation [22][23][24][25]. ...
... In addition, the Mediterranean healthy eating, aging and lifestyle (MEAL) study reported an inverse relationship between intake of polyphenols and risk of depression [49]. Generally, phytochemicals by regulating dopaminergic brain pathways, enhancing serotonin and dopamine levels in the hippocampus and prefrontal cortex, and reducing monoamine oxidase (MAO) activity may improve depressive symptoms [19][20][21]50]. ...
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Background There is increasing evidence that the dietary intake of phytochemicals is inversely associated with severity of depression and positively associated with quality of life (QoL). The present study investigated the relationship between dietary phytochemical index (DPI) with depression and QoL scores in Iranian adolescent girls. Methods A total of 733 adolescent girls from Mashhad and Sabzevar cities in northeastern Iran were entered into this cross-sectional study. Assessment of depression and QoL was performed utilizing the Beck Depression Inventory (BDI) and SF-12v2 questionnaire, respectively. Assessment of dietary intake was undertaken by a qualified dietitian, using a validated food-frequency questionnaire (FFQ) containing 168 food items. To explore the association between DPI with QoL and depression, logistic regression was used in crude and adjusted models. Results The participants in the fourth quartile of DPI compared with the first quartile had a 50% lower odds of depression (OR: 0.50; 95% CI: 0.30-0.84, P = 0.009) This relation remained significant in all adjusted models. The adolescents in highest quartile of DPI compared with the first quartile had 38% lower odds of poor QoL (OR: 0.62; 95% CI: 0.41-0.94, P = 0.02). This association remained significant in adjusted models I and II, but not after adjusting for all confounding variables (OR: 0.67; 95% CI: 0.43-1.02, P = 0.06) (Model III). Conclusions DPI was inversely associated with risk of depression. The association between DPI score and QoL remained unclear. Further prospective and interventional studies are required.
... Particularly, there are several previous studies that investigated the association between TREK-1 and depression, and inhibitors of TREK-1 have been considered to have antidepressant effects. Clearly, antidepressant effects have been reported in both TREK-1-deficient mice and mice treated with fluoxetine, curcumin, spadin, SID1900, and TKDC, which are well-known TREK-1 inhibitors [2,[4][5][6][7][8]. Genotypes of mice were identified using genomic deoxyribonucleic acid. ...
... Suppression of overall brain TREK-1 in TREK-1 knockout mice or treatment with TREK-1 inhibitors has shown effective antidepressant effects [2,[4][5][6][7][8]. Indeed, TREK-1 is considered a background potassium channel, and inhibition of this channel can increase the activity of the expressing neurons. ...
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TWIK-related potassium channel-1 (TREK-1) is broadly expressed in the brain and involved in diverse brain diseases, such as seizures, ischemia, and depression. However, the cell type-specific roles of TREK-1 in the brain are largely unknown. Here, we generated a Cre-dependent TREK-1 knockdown (Cd-TREK-1 KD) transgenic mouse containing a gene cassette for Cre-dependent TREK-1 short hairpin ribonucleic acid to regulate the cell type-specific TREK-1 expression. We confirmed the knockdown of TREK-1 by injecting adeno-associated virus (AAV) expressing Cre into the hippocampus of the mice. To study the role of hippocampal neuronal TREK-1 in a lipopolysaccharide (LPS)-induced depression model, we injected AAV-hSyn-BFP (nCTL group) or AAV-hSyn-BFP-Cre (nCre group) virus into the hippocampus of Cd-TREK-1 KD mice. Interestingly, the immobility in the tail suspension test after LPS treatment did not change in the nCre group. Additionally, some neurotrophic factors (BDNF, VEGF, and IGF-1) significantly increased more in the nCre group compared to the nCTL group after LPS treatment, but there was no difference in the expression of their receptors. Therefore, our data suggest that TREK-1 in the hippocampal neurons has antidepressant effects, and that Cd-TREK-1 KD mice are a valuable tool to reveal the cell type-specific roles of TREK-1 in the brain.
... В таких случаях куркумин способен не только смягчать поведенческие нарушения, но и повышать содержание дофамина, норадреналина и серотонина в мозге животных [41]. В тестах вынужденного плавания и принудительного подвешивания (tail suspension) куркумин проявлял АД-подобную активность как при однократном [35,[41][42][43], так и при повторном (хроническом) введении [38,39,44]. При этом эффект куркумина был сходным с действиями флуоксетина и имипрамина [45]. ...
... Куркумин дозозависимо повышал серотонин, а при более высоких дозах увеличивал уровень дофамина, но не норадреналина. Куркумин также был способен ингибировать моно аминооксидазу MAO-A, а в более высоких дозах MAO-B [42]. Полагают, что АД-подобные эффекты куркумина в FS-тесте связаны с серотонинергической системой, возможно, из-за взаимодействия с 5-HT 1A/1B -и 5-HT 2C -рецеп то ра ми [43]. ...
Article
Curcumin, a natural compound found in the rhizomes of turmeric, has a pronounced anti-inflammatory activity. Rodent models of depression show that this activity is similar to the effect of antidepressants (AD). Experimental data indicate that this activity may be related to the effect of curcumin on the monoamine cycle, oxidative and nitrosative stress, neurogenesis, hypothalamic-pituitary-adrenal, and immune systems. A number of meta-analyzes indicate the effectiveness of the combined use of curcumin with antidepressants in the treatment of depression. The mechanism of action of curcumin, as well as the prospects for its further use are considered.
... Curcumin (CUR) is known for its miscellany of immunomodulatory, anti-inflammatory, antioxidant, and neuroprotective effects. 16 Kulkarni et al 17 have referred to the relationship between the antidepressant effect of CUR and monoaminergic systems. In the study by Mazzio et al, 18 CUR was shown to have the ability to restore monoaminergic function and inhibit the activity of MAO. ...
... Furthermore, NE levels were normalized in the limbic system, midbrain, and plasma, and elevated in cerebellum and pons-medulla in CUR-treated rats.These data advocate that CUR impacted the synthesis or metabolism of DA and NE to maintain ordinary dopaminergic-adrenergic functions.31 In accordance, Kulkarni et al and Chang et al16,17 referred to CUR antidepressant activity through the monoaminergic neurotransmitter pathway, following an olfactory bulbectomy in a forced swimming test model of depression. The behavioural findings of this study showed that horizontal and vertical activities were improved after treatment with CUR. ...
Article
Anti‐inflammatory products may represent the future for depressive disorder therapies. Curcumin (CUR) is a polyphenol and an active component of the turmericplant Curcuma longa. The aim of this study was to investigate the impact of CUR,as a natural anti‐inflammatory agent, on neuro‐inflammation related to depression and compare it with the effects of fluoxetine (FLX) and estradiol (E2) in ovariectomized (OVX) rats.The experimental animals were divided into the following five treatment groups (n=10): sham‐operated, OVX, OVX‐E2 (100 μg/kg, i.m., every other day), OVX‐FLX (20 mg/kg, i.p., daily), and OVX‐CUR (100 mg/kg, p.o., daily). The results indicated that CUR improved the animals’ performances in theopen field test and modulated dopamine (DA) and norepinephrine levels in several brain regions compared with the OVX group. CUR resulted in the down‐regulation of monoamine oxidase b and up‐regulation of tyrosine hydroxylase, as well asDA receptor mRNA in the limbic region. In addition, CURsignificantly attenuated the production of serum corticosterone hormone, tumor necrosis factor‐alpha, interleukin‐β1, interleukin‐6, and nitric oxide in the limbic system. Furthermore, CUR normalized malondialdehyde levels and led to a significant upsurge in total antioxidant capacity, compared with the OVX group. Consequently, CUR, besides being harmless, was efficient against inflammation and oxidative‐nitrosative stress, showing a greater effect on DA receptor expression than FLX and E2 in OVX rats.
... Since K2P heterodimeric channels are known to be regulated by regulators specific only for single subunit isoforms [11,36,[45][46][47][48][49], even if the TWIK-1 isoform is not modulated, astrocytic passive conductance mediated by TWIK-1/TREK-1 heterodimeric channels could be regulated by spadin, a specific TREK-1 inhibitor (Figures 6 and 7). From these results, it is also possible that other TREK-1 inhibitors such as fluoxetine, curcumin, SID1900, and TKCD can affect TWIK-1/TREK-1 mediated astrocytic passive conductance, which should be examined in further studies [24,[50][51][52]. ...
... Several previous studies have demonstrated that TREK-1 is involved in depression [23] and TREK-1 inhibitors have been considered to have antidepressant effects [23,27,[50][51][52][53]. Clearly, antidepressant effects have been reported in both TREK-1 KO mice and mice treated with spadin, a specific TREK-1 inhibitor [23,53]. ...
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Astrocytes, the most abundant cell type in the brain, are non-excitable cells and play critical roles in brain function. Mature astrocytes typically exhibit a linear current–voltage relationship termed passive conductance, which is believed to enable astrocytes to maintain potassium homeostasis in the brain. We previously demonstrated that TWIK-1/TREK-1 heterodimeric channels mainly contribute to astrocytic passive conductance. However, the molecular identity of astrocytic passive conductance is still controversial and needs to be elucidated. Here, we report that spadin, an inhibitor of TREK-1, can dramatically reduce astrocytic passive conductance in brain slices. A series of gene silencing experiments demonstrated that spadin-sensitive currents are mediated by TWIK-1/TREK-1 heterodimeric channels in cultured astrocytes and hippocampal astrocytes from brain slices. Our study clearly showed that TWIK-1/TREK-1-heterodimeric channels can act as the main molecular machinery of astrocytic passive conductance, and suggested that spadin can be used as a specific inhibitor to control astrocytic passive conductance.
... However, it has also been reported that dietary intake of polyphenol compounds attenuates oxidative stress and reduces the risk of developing related neurodegenerative diseases such as AD, Parkinson's disease, stroke, multiple sclerosis, and Huntington's disease [34]. Indeed, polyphenols and natural compounds can modulate various neurotransmitter systems in the brain; for instance, curcumin, which modulates serotoninergic and dopaminergic neurotransmission, acts as an antidepressant agent via regulating the levels of MAO-A and MAO-B enzymes [35,36]. So far, several studies exploring the ability of polyphenols in the management of neurodegenerative disorder and major depression [19] have been undertaken. ...
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In this study, we explored the ability of Annurca apple flesh polyphenol extract (AFPE) to affect the activity of key enzymes involved in neurodegenerative disorders—in particular, Acetyl- and Butirryl-cholinesterases, and type A and B monoamine oxidase. The effect of AFPE on enzyme activity was analyzed by in vitro enzyme assays, and the results showed concentration-dependent enzyme inhibition, with IC50 values corresponding to 859 ± 18 µM and 966 ± 72 µM for AChE and BuChE respectively, and IC50 corresponding to 145 ± 3 µM and 199 ± 7 µM for MAO-A and MAO-B, respectively, with a preference for MAO-A. Moreover, in this concentration range, AFPE did not affect the viability of human neuroblastoma SH-SY5Y and fibroblast BJ-5ta cell lines, as determined by an MTT assay. In conclusion, our results demonstrate that AFPE shows the new biological properties of inhibiting the activity of enzymes that are involved in brain functions, neurodegenerative disorders, and aging.
... The mechanism by which curcumin counteracted the effect of risperidone on locomotor activity are unknown, but it has been reported that curcumin supplementation reduces diabetes induced alteration of the dopamine D2 receptor (Kumar et al. 2010), which is involved with antipsychotics induced motor deficit. Curcumin could delay dopamine degradation by inhibiting the activity of MAO-A and MAO-B enzymes (Rajeswari and Sabesan 2008;Kulkarni et al. 2008;Bhutani et al. 2009), resulting in an increase in extracellular dopamine concentration available to stimulate D2 receptors and to improve motricity. It has been reported that the decrease in physical activity in mice treated with risperidone was due to sedation (Klingerman et al. 2014). ...
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Antipsychotics, such as risperidone, increase food intake and induce alteration in glucose and lipid metabolism concomitantly with overweight and body fat increase, these biological abnormalities belong to the metabolic syndrome definition (high visceral adiposity, hypertriglyceridemia, hyperglycemia, low HDL-cholesterol and high blood pressure). Curcumin is a major component of traditional turmeric (Curcuma longa) which has been reported to improve lipid and glucose metabolism and to decrease weight in obese mice. We questioned the potential capacity of curcumin, contained in Curcuma longa extract (Biocurcuma™), to attenuate the risperidone-induced metabolic dysfunction. Two groups of mice were treated once a week, for 22 weeks, with intraperitoneal injection of risperidone (Risperdal) at a dose 12.5 mpk. Two other groups received intraperitoneal injection of the vehicle of Risperdal following the same schedule. Mice of one risperidone-treated groups and of one of vehicle-treated groups were fed a diet with 0.05% Biocurcuma™ (curcumin), while mice of the two other groups received the standard diet. Curcumin limited the capacity of risperidone to reduce spontaneous motricity, but failed to impede risperidone-induced increase in food intake. Curcumin did not reduce the capacity of risperidone to induce weight gain, but decreased visceral adiposity and decreased the risperidone-induced hepatomegaly, but not steatosis. Furthermore, curcumin repressed the capacity of risperidone to induce the hepatic over expression of enzymes involved in lipid metabolism (LXRα, FAS, ACC1, LPL, PPARγ, ACO, SREBP2) and decreased risperidone-induced glucose intolerance and hypertriglyceridemia. Curcumin decreased risperidone-induced increases in serum markers of hepatotoxicity (ALAT, ASAT), as well as of one major hepatic pro-inflammatory transcription factor (NFκB: p105 mRNA and p65 protein). These findings support that nutritional doses of curcumin contained in Curcuma longa extract are able to partially counteract the risperidone-induced metabolic dysfunction in mice, suggesting that curcumin ought to be tested to reduce the capacity of risperidone to induce the metabolic syndrome in human.
... To our knowledge, no dietary pattern similar to Traditional-Indian-Confinement pattern has been examined in relation to PPD in previous literature for direct comparison. However, key food groups of Traditional-Indian-Confinement diet, such as Indian herbs and seed herbs (e.g., saffron [48,49], fenugreek [50]), as well as curcumin [51,52] present in curry dishes have previously been reported to be effective in alleviating depressive symptoms via their anti-inflammatory [49,53], neuroprotective [54], serotonergic [55,56], and hypothalamic pituitary adrenal (HPA) regulation effects [57]. The Traditional-Indian-Confinement diet also comprises of legumes and pulses and ethnic bread (e.g., chapatti, thosai, idli, and naan), which are rich in B-group vitamins, are crucial for the synthesis of monoamine neurotransmitters and may have helped to establish protection against PPD symptoms [20,58,59]. ...
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Diet in the first month postpartum, otherwise known as "the confinement diet" in Asia, has unique characteristics that are influenced by traditions, cultures, and beliefs. We aimed to characterize dietary patterns during confinement period in a multi-ethnic Asian cohort and examined their associations with postpartum depression (PPD) and anxiety (PPA). Dietary intakes of 490 women were ascertained in the first month postpartum using 3-day food diaries and dietary patterns were derived by factor analysis. Participants completed the Edinburgh Postnatal Depression Scale (EPDS) and State-Trait Anxiety Inventory (STAI) at three months' postpartum; higher scores are indicative of more depressive and anxiety symptoms, respectively. Four dietary patterns were identified: Traditional-Chinese-Confinement diet, Traditional-Indian-Confinement diet, Eat-Out diet and Soup-Vegetables-Fruits diet. The Traditional-Indian-Confinement diet was associated with less PPD symptoms [β (95% CI) -0.62 (-1.16, -0.09) EPDS score per SD increase in diet score] and a non-significant trend with reduced probable PPD (EPDS scores ≥ 13) [OR (95% CI) 0.56 (0.31, 1.01)]. The Soup-Vegetables-Fruits diet was associated with less PPA symptoms [β (95% CI) -1.49 (-2.56, -0.42) STAI-state score]. No associations were observed for other dietary patterns. Independent of ethnicity, adherence to the Traditional-Indian-Confinement diet that is characterized by intake of herbs and legumes, and Soup-Vegetables-Fruits diet high in fruits, vegetables and fish during the postpartum period were associated with less PPD and PPA symptoms, respectively.
... Patients suffering from depression treated with infliximab, an anti-TNF antibody, for longer period of time, also benefited from the therapy in terms of improving their mental state (Raison et al. 2013). Curcumin, a nutrient present in plants of the ginger family, may also contribute to the reduction of depressive symptoms when supplemented with classic antidepressant treatment (Yu et al. 2015), most likely by inhibiting the production of inflammatory mediators, such as prostaglandins, leukotrienes or nitric oxide and increasing in the concentration of biogenic amines in the brain (Kulkarni et al. 2008). ...
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Depression is one of the most frequently diagnosed condition in psychiatry. Despite the availability of many preparations, over 30% of treated patients do not achieve remission. Recently the emphasis is put on the contribution of the body’s inflammatory response as one of the causes of depression. The interactions between nervous and immune systems are the main issue addressed by psychoneuroimmunology. In patients suffering from depression changes in the plasma concentrations of cytokines and in the number and level of activation of immune cells has been found. Attention is paid to the high levels of pro-inflammatory cytokines, the prevalence of Th1 responses to Th2, weakening of NK cell cytotoxicity and changes in lymphocyte proliferation and apoptosis. A number of studies focus on influence of antidepressants and non-standard methods of depression treatment, such as ketamine infusion, on patients’ immunology. Many of them seem to regulate the immune responses. The study results encourage to look for new ways to treat depression with immunomodulatory drugs. In this article authors present the current knowledge about immune system changes accompanying depression as well as the study results showing the influence of drugs on the immune system, especially in the context of reducing the symptoms of depression.
... Curcumin has been extensively used for centuries as a spice, food preservative, and yellow colorant in the food, drugs, and cosmetic industries (Shishu and Maheshwari, 2010). Beside its culinary uses, curcumin has been considered a medicinal remedy in several countries for centuries, owing to its various physiological activities, such as antioxidant (Menon and Sudheer, 2007;Feng and Liu, 2009;Nabavi et al., 2011;Nabavi et al., 2012;Shakeri and Boskabady, 2017), anti-depressant (Kulkarni et al., 2008;Bhutani et al., 2009;Kulkarni et al., 2009), anti-inflammatory (Menon and Sudheer, 2007;Shakeri and Boskabady, 2017), antimicrobial (Mathew and Hsu, 2018;da Silva et al., 2018), anticancer (Bar-Sela et al., 2010;Wilken et al., 2011;Vallianou et al., 2015), and immunomodulatory properties (Gautam et al., 2007;Shakeri and Boskabady, 2017). ...
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Encapsulated curcumin (ENCC) was prepared from a commercial curcuminoids complex and was evaluated for its intestinal permeability and hepatoprotective effects. Intestinal permeability was evaluated using a Caco-2 intestinal cell monolayer system and the non-everted gut sac method. The hepatoprotective effect was evaluated in experimental rats administered alcohol for 4 weeks. The intestinal permeability results suggested that encapsulation is a useful method for enhancing adsorption of curcumin via the intestinal epithelium. ENCC administration resulted in the significant reduction of various serum indicators. Notably, most of the indicators elevated by ethanol decreased below normal levels when rats were administered a high dose of ENCC. Oral administration of ENCC also augmented the activity of glutathione peroxidase in the liver, and both normal curcumin and ENCC significantly alleviated high levels of malondialdehyde. Our results demonstrate a significant hepatoprotective effect of ENCC in vivo owing to its ability to improve bioavailability of curcumin.
... Many animal studies demonstrated the beneficial effect of polyphenols, natural antioxidant compounds found in plant-based foods, in depressive-like [87][88][89] and in ASD-like [90] behavior. In a rat model of depression induced by corticosterone administration, treatment with curcumin, a known potent plant antioxidant, significantly suppressed depression-like behavior and delayed the deterioration of brain Brain-derived neurotrophic factor (BDNF) levels [87]. ...
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S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.
... In rats, acute curcumin (5 and 10 mg/ Kg, p.o. and 20-80 mg/kg, i.p.) produced a significant inhibition of the immobility in the tail suspension test, forced swimming, and locomotor test. At the same time, it increased dopamine, serotonin, and noradrenaline levels, inhibiting both monoamine oxidase types in the rat brain [64,65]. In zebrafish larval, has been shown that antidepressants commonly affect swim speeds and resting, and differentially affect other behaviors depending upon the exposure period. ...
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Zebrafish larvae have been widely used in neuroscience and drug research and development. In the larval stage, zebrafish present a broad behavioral repertoire and physiological responses similar to adults. Curcumin (CUR), a major component of Curcuma longa L. (Zingiberaceae), has demonstrated the ability to modulate several neurobiological processes relevant to mental disorders in animal models. However, the low bioavailability of this compound can compromise its in vivo biological potential. Interestingly, it has been shown that micronization can increase the biological effects of several compounds. Thus, in this study, we compared the effects of acute exposure for 30 min to the following solutions: water (control), 0.1% DMSO (vehicle), 1 μM CUR, or 1 μM micronized curcumin (MC) in zebrafish larvae 7 days post-fertilization (dpf). We analyzed locomotor activity (open tank test), anxiety (light/dark test), and avoidance behavior (aversive stimulus test). Moreover, we evaluated parameters of oxidative status (thiobarbituric acid reactive substances and non-protein thiols levels). MC increased the total distance traveled and absolute turn angle in the open tank test. There were no significant differences in the other behavioral or neurochemical outcomes. The increase in locomotion induced by MC may be associated with a stimulant effect on the central nervous system, which was evidenced by the micronization process.
... [PMID:12680238], and has been shown to target multiple signaling molecules while also demonstrating activity at the cellular level, which has helped to support curcuma longa multiple health benefits. 15 Curcumin has been shown to benefit pain and depression through inhibiting monoamine oxidase, modulating the level of serotonin and monoamine, inhibiting glutamate release in the prefrontal cortex, [16][17][18] and activating MAPK/ERK-dependent BDNF expression in the amygdala region. 19 However, a detailed metabolic profiling for the anti-depression effects of curcumin has not been done yet. ...
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Background: Depression is a prevalent and complex psychiatric disorder with high incidence in patients with chronic pain. The underlying pathogenesis of chronic pain-induced depression is complicated and remains largely unclear. An integrated analysis of endogenous substance-related metabolisms would help to understand the molecular mechanism of chronic pain-induced depression. Curcumin was reported to exert various health benefits, such as anti-depression, antioxidant, antineoplastic, analgesia, and anti-inflammation. Objective: The aim of this study was to analyze the biomarkers related to depression in serum and to evaluate the anti-depression properties of curcumin in a chronic pain-induced depression model of rats. Design: This is a randomized, controlled experiment. Setting: This study was conducted at the Experimental Animal Center, Beijing Friendship Hospital, Capital Medical University. Methods: Trigeminal neuralgia (TN) was produced by injecting 4 µL, 10% cobra venom saline solution into the infraorbital nerve (ION). Curcumin was administered by gavage twice a day from post-operation day (POD) 15 to POD 42. Mechanical allodynia was assessed using von Frey filaments. Sucrose preference and forced swimming tests were performed to evaluate depression-like behaviors. The metabolomics analysis was preceded by LCMS-IT-TOF and multivariate statistical methods for sample detection and biomarker screening. Results: Cobra venom intra-ION injection led to chronic mechanical allodynia, reduced sucrose preference, and prolonged immobility during forced swimming. Curcumin treatment alleviated chronic mechanical allodynia, regained sucrose preference, and reduced immobility time. Differential analysis identified 30 potential metabolites changed under TN condition. The integrated analyses further revealed two major metabolic changes by comparing the serums from sham operated rats, TN rats, and TN rats treated with curcumin: 1) ether lipid metabolism; and 2) glycerophospholipid metabolism, and suggested that curcumin may improve chronic pain-induced depression by regulating these two types of lipid metabolisms. Conclusion: Ether lipid and glycerophospholipid metabolism might be two of the pathways with the most potential related to chronic pain induced-depression; and curcumin could alleviate chronic pain induced-depression by modulating these two pathways. These results provide further insights into the mechanisms of chronic pain-induced depression and may help to identify potential targets for anti-depression properties of curcumin.
... Another study has shown that nano-curcumin can contribute to the increased rate of inflammatory cytokines especially IL-1β and IL-6 mRNA expression and cytokine secretion in COVID-19 patients [29]. Although curcumin has low absorption, the addition of piperine improves its absorption and bioavailability of [30][31][32]. It is revealed that administration of piperine with curcumin resulted in 2000% increase in bioavailability of curcumin [33]. ...
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Background COVID-19 pandemic has made the disease a major global problem by creating a significant burden on health, economic, and social status. To date, there are no effective and approved medications for this disease. Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19. Methods Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days. Results Mean changes in complete blood count, liver enzymes, blood glucose levels, lipid parameters, kidney function, and c-reactive protein (CRP) were not significantly different between the two groups. There was a significant improvement in health status, including dry cough, sputum cough, ague, sore throat, weakness, muscular pain, headache, and dyspnea at week 2 in both curcumin-piperine and placebo groups ( P value < 0.05); however, the improvement in weakness was more in the curcumin-piperine group than with placebo group ( P value 025). Conclusion The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness. However, in this study, curcumin-piperine co-supplementation could not significantly affect the other indices, including biochemical and clinical indices. Trial registration Iranian Registry of Clinical Trials IRCT20121216011763N46 . 2020-10-31
... Moreover, the seeds of the Ginkgo biloba have been employed in traditional Chinese medicine for their neuro-protective effects [39]. Curcuma has been incorporated in both traditional Indian and Chinese medicine in an effort to regulate stress and mood disorders [40,41]. Chlorophytum comosum has traditionally been used in traditional medicinal preparations in India, China, and Africa, with the constituent stigmasterol exerting neuroprotective effects [42]. ...
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Saffron is a valued herb, obtained from the stigmas of the C. sativus Linn (Iridaceae), with therapeutic effects. It has been described in pharmacopoeias to be variously acting, including as an anti-depressant, anti-carcinogen, and stimulant agent. The therapeutic effects of saffron are harbored in its bioactive molecules, notably crocins, the subject of this paper. Crocins have been demonstrated to act as a monoamine oxidase type A and B inhibitor. Furthermore, saffron petal extracts have experimentally been shown to impact contractile response in electrical field stimulation. Other research suggests that saffron also inhibits the reuptake of monoamines, exhibits N-methyl-D-aspartate antagonism, and improves brain-derived neurotrophic factor signaling. A host of experimental studies found saffron/crocin to be similarly effective as fluoxetine and imipramine in the treatment of depression disorders. Saffron and crocins propose a natural solution to combat depressive disorders. However, some hurdles, such as stability and delivery, need to be overcome.
... Curcumin has been reported to mitigate symptoms of depression by enhancing neurogenesis in the hippocampus and frontal cortex (94). It also inhibits the action of monoamine oxidase enzymes, thus preventing the breakdown of monoaminergic neurotransmitters, thereby increasing serotonin and dopamine levels (140). Epigallocatechin gallate from green tea has been reported to alleviate symptoms of stress and depression (93). ...
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There is a strong relationship between a healthy diet and mental well-being. Several foods and food compounds are known to modulate biomarkers and molecular mechanisms involved in the aetiogenesis of several mental disorders, and this can be useful in containing the disease progression, including its prophylaxis. This is an updated systematic review of the literature to justify the inclusion and recognition of nutrition in the management of psychiatric illnesses. Such foods and their compounds include dietary flavanols from fruits and vegetables, notable antioxidant and anti-inflammatory agents, probiotics (fermented foods) known to protect good gut bacteria, foods rich in polyunsaturated fatty acids (e.g., Omega-3), and avoiding diets high in saturated fats and refined sugars among others. While the exact mechanism(s) of mitigation of many nutritional interventions are yet to be fully understood, the evidence-based approach warrants the inclusion and co-recognition of nutrition in the management of psychiatric illnesses. For the greater public health benefit, there is a need for policy advocacy aimed at bridging the knowledge gap and encouraging the integration of nutritional intervention with contemporary therapies in clinical settings, as deficiencies of certain nutrients make therapy difficult even with appropriate medication.
... Antiprostate cancer property of DHZ has been proven both in vitro as well as in vivo [18]. The antidepressant activity of curcumin has been widely studied and has been linked to the MAO inhibitory activity [19], through the serotonergic and dopaminergic system [20]. Curcumin was found to have potent inhibitory activity for both MAO-A and MAO-B enzymes [21]. ...
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Background Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo. Method The binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography–mass spectrometry. Results DHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly ( p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential. Conclusion DHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.
... To detect MAO-A level, in a cuvette 2.75 ml of tris buffer (pH 7.4), 150 µL of brain supernatant and 100 µL of 5-hydroxytryptamine were mixed, and absorbance was noted at 280 nm for 5 min against the blank solution. Similarly, for detecting MAO-B level 2.75 ml of tris buffer, 150 µL of brain supernatant and 100 µL of benzylamine were mixed, and absorbance was noted at 242 nm for 5 min against the blank solution (42). The activity of MAO-A and B were expressed in nmoles/mg of protein. ...
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Objective Monoamine Oxidase (MAO), which catalyzes the oxidative deamination of amines present in the brain and peripheral tissues, is involved in the metabolism of monoamines and is vital for cognition. This study was designed to examine the protective effect of Apple Cider Vinegar (ACV) on MAO and amine neurotransmitters such as dopamine (DA), serotonin (5-HT), non-adrenaline (NA) levels. Method In this experiment, out of five groups, three groups of animals were pretreated with one of the test drugs each i.e., Chrysin (10 mg/kg), ACV (0.7% v/v) and Rivastigmine (2.5 mg/kg) along with Zn with high fat diet (HFD) for 3 months and the rest two groups were that of control and disease induced. After the treatment period, mice were examined for MAO-A & B, DA, 5-HT and NA level estimation. Results The results showed that Zn with HFD had induced a significant increase (p < 0.01, p < 0.001) in MAO-A & B levels and a significant decrease (p < 0.001) in the levels of 5-HT, DA, and NA. Pretreatment of test drugs with Zn with HFD caused a restoration activity and a significant decrease (p < 0.01, p < 0.05) in MAO-A & B levels and a significant increase (p < 0.05, p < 0.01, p < 0.001) in the level of DA, 5HT and NA as compared to the Zn treated group. Amongst all three test drugs mentioned above, the ACV-treated group showed the most improvement during pretreatment. Conclusions The findings suggest that ACV, might prove to be a beneficial nutraceutical & provide a protective effect against Alzheimer’s disease (AD)-like neurological diseases.
... 114 Animal experiments have also shown that curcumin modulates the levels of norepinephrine, dopamine, and serotonin in the brain. 115,116 In addition, it offers neuroprotective effects against arsenic-induced cholinergic dysfunctions, 117 reverses cognitive impairments induced by chronic mild stress, and induces the proliferation of astrocytes ...
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... Carvacrol (Supplementary Figure S3AN) (aromatic plant extract) caused a dopaminergic systemmediated antidepressant effect leading to elevated levels of serotonin (5-HT) and dopamine (Melo et al., 2011;Zotti et al., 2013). On the contrary, curcumin (Supplementary Figure S3AO) exerts its antidepressant activity via the serotonergic receptor system (5-HT1A/1B and 5-HT2C) causing an elevation in the serotonin (5-HT) levels (Wang R. et al., 2008;Kulkarni et al., 2008). The otherwise altered 5-HT1A mRNA (hippocampus) was also reversed in curcumin-treated mice models of depression (Xu et al., 2007). ...
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Background . Depression is a recurrent, common, and potentially life-threatening psychiatric disease related to multiple assignable causes. Although conventional antidepressant therapy can help relieve symptoms of depression and prevent relapse of the illness, complementary therapies are required due to disadvantage of the current therapy such as adverse effects. Moreover, a number of studies have researched adjunctive therapeutic approaches to improve outcomes for depression patients.Purpose. One potential complementary method with conventional antidepressants involves the use of medicinal herbs and phytochemicals that provide therapeutic benefits. Studies have revealed beneficial effects of medical herbs and phytochemicals on depression and their central nervous system mechanism. Here, we summarize the current knowledge of the therapeutic benefits of phytochemicals and medicinal herbs against depression and describe their detailed mechanisms.Sections. There are two sections, phytochemicals against depression and medical herbs against depression, in this review.Conclusion. Use of phytomedicine may be an alternative option for the treatment of depression in case conventional drugs are not applicable due to their side effects, low effectiveness, or inaccessibility. However, the efficacy and safety of these phytomedicine treatments for depression have to be supported by clinical studies.
Chapter
Curcumin mediates its neuroprotective effects not only in neurotraumatic disorders (stroke, spinal cord injury, traumatic brain injury, and epilepsy), but also in Parkinson disease, Huntington disease, and prion diseases. In addition, curcumin also promote its beneficial effects in neuropsychological disorders (depression, biopolar disorders, and tardive dyskinesia). The mechanism associated with neuroprotective action of curcumin is not fully understood. However, it is becoming increasingly evident that anti-inflammatory and antioxidant properties of curcumin may be responsible for neuroprotective effects. At the molecular level, neuroprotective effects of curcumin are accompanied by downregulating activities of phospholipases, lipooxygenase, cyclooxygenase-2, which lead to low levels of leukotrienes, thromboxanes, prostaglandins. In addition, curcumin also inhibits the expression of TNF-α, IL-12, MCP-1, and interferon-inducible protein. In addition, curcumin also modulates various neurotransmitter levels in the brain.
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Curcumin is extensively used in the prevention and treatment of various diseases. Recently, growing attention has been paid to the use of curcumin as a neurogenic and neuroprotective agent. This review study aimed to collect and categorize the recent findings regarding the effects of curcumin on various neurological diseases through the induction of neural stem cell proliferation and differentiation. In addition, we have discussed the molecular mechanisms modulated by curcumin that contribute to this efficacy and have summarized the recent advancements in the novel delivery strategies used to improve the induction of neural stem cells by curcumin. This article is protected by copyright. All rights reserved
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In recent times, many scientists have given great attention to nutraceuticals (complementary medicine) as it widely used for promoting health status. In particular for the prevention and treatment of various neurological diseases or disorders without or less adverse effects. The current mini-review was intended to compile all popular (major) nutraceuticals against various neurodegenerative diseases (NDDs) including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) with special reference to clinical trials. Preliminary reviews indicated that nutraceuticals like curcumin, resveratrol, Epigallocatechin-3-gallate (EGCG), Coenzyme Q10, ω-3 FA (DHA/EPA/ALA), showed better neuroprotective activity against various NDDs in human setting (clinical trial). Hence this contribution will focus only on those popular nutraceuticals with proposed brief mechanisms (antioxidant, anti-inflammatory, mitochondrial homeostasis, autophagy regulation, promote neurogenesis) and its recommendation. This mini-review would aid common people to choose better nutraceuticals to combat various NDDs along with standard neuroprotective agents and modified lifestyle pattern.
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Polyphenols, present in a broad range of plants, have been thought to be responsible for many beneficial health effects, such as anti-depressant. Despite polyphenols can be absorbed in small intestine directly, most of them have low bioavailability and reach the large intestine without any modifications due to their complex structures. The interactions between microbial communities and polyphenols in the intestine is important for the latter to exert antidepressant effects. Gut microbiota can improve the bioavailability of polyphenols, in turn, polyphenols can maintain the intestinal barrier, as well as the community of the gut microbiota in normal status. Furthermore, gut microbita catabolize polyphenols to more active, better-absorbed metabolites, further ameliorate depression through the microbial-gut-brain (MGB) axis. Based on these evidences, the review illustrated the potential role of gut microbiota in the processes of polyphenols or their metabolites acting as antidepressants, and further envisioned the gut microbiota as the therapeutic targets for depression.
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Context: Depression is a severe mental illness caused by a deficiency of dopamine and serotonin. Cannabis sativa L. (Cannabaceae) has long been used to treat pain, nausea, and depression. Objective: This study investigates the anti-depressant effects of C. sativa (hemp) seed ethanol extract (HE) in chlorpromazine (CPZ)-induced Drosophila melanogaster depression model. Materials and methods: The normal group was untreated, and the control group was treated with CPZ (0.1% of media) for 7 days. The experimental groups were treated with a single HE treatment (0.5, 1.0, and 1.5% of media) and a mixture of 0.1% CPZ and HE for 7 days. The locomotor activity, behavioural patterns, depression-related gene expression, and neurotransmitters level of flies were investigated. Results: The behavioural patterns of individual flies were significantly reduced with 0.1% CPZ treatment. In contrast, combination treatment of 1.5% HE and 0.1% CPZ significantly increased subjective daytime activity (p < 0.001) and behavioural factors (p < 0.001). These results correlate with increased transcript levels of dopamine (p < 0.001) and serotonin (p < 0.05) receptors and concentration of dopamine (p < 0.05), levodopa (p < 0.001), 5-HTP (p < 0.05), and serotonin (p < 0.001) compared to those in the control group. Discussion and conclusions: Collectively, HE administration alleviates depression-like symptoms by modulating the circadian rhythm-related behaviours, transcript levels of neurotransmitter receptors, and neurotransmitter levels in the CPZ-induced Drosophila model. However, additional research is needed to investigate the role of HE administration in behavioural patterns, reduction of the neurotransmitter, and signalling pathways of depression in a vertebrate model system.
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Depression is one of the most common but serious psychiatric disorders affecting millions of people globally, which has become increasingly prevalent during the past few decades. To alleviate this challenging health and social burden, various therapeutic strategies have been developed to achieve efficient treatments for depression. In particular, plenty of chemical ingredients of natural origin have been investigated as new direct antidepressants or served as adjuvants to improve the current treatment outcomes of existing antidepressant drugs. Among them, curcumin, a natural compound derived from the herb Curcuma longa, exhibits a wide range of pharmacological properties and has been considered a potent antidepressant drug with diverse mechanisms including monoaminergic imbalances (associated with serotonin, dopamine, noradrenaline, and glutamate), effect on neurotransmitters, neuroprogression, the hypothalamic‐pituitary‐adrenal (HPA) axis disturbances, dysregulated inflammation and immune pathways, oxidative and nitrosative stress, and mitochondrial disturbances. In this review, multiple potential mechanisms of curcumin for treating depression demonstrated in either animal or human studies are summarized. To better understand the significant role of curcumin, specific emphasis will be placed on the etiopathogenesis of depression. Finally, current preclinical/clinical trials and ongoing challenges of curcumin used for antidepressant treatments will be discussed and their future outlooks will be briefly presented.
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Background Major depressive disorder (MDD) is a severe mental disorder related to the deficiency of monoamine neurotransmitters, particularly to abnormalities of 5-HT (5-hydroxytryptamine, serotonin) and its receptors. Our previous study suggested that acute treatment with a novel curcumin derivative J147 exhibited antidepressant-like effects by increasing brain derived neurotrophic factor (BDNF) level in the hippocampus of mice. The present study expanded upon our previous findings and investigated the antidepressant-like effects of sub-acute treatment of J147 for 3 days in male ICR mice and its possible relevancy to 5-HT1A and 5-HT1B receptors and downstream cAMP-BDNF signaling.MethodsJ147 at doses of 1, 3, and 9 mg/kg (via gavage) was administered for 3 days, and the anti-immobility time in the forced swimming and tail suspension tests (FST and TST) was recorded. The radioligand binding assay was used to determine the affinity of J147 to 5-HT1A and 5-HT1B receptor. Moreover, 5-HT1A or 5-HT1B agonist or its antagonist was used to determine which 5-HT receptor subtype is involved in the antidepressant-like effects of J147. The downstream signaling molecules such as cAMP, PKA, pCREB, and BDNF were also measured to determine the mechanism of action.ResultsThe results demonstrated that sub-acute treatment of J147 remarkably decreased the immobility time in both the FST and TST in a dose-dependent manner. J147 displayed high affinity in vitro to 5-HT1A receptor prepared from mice cortical tissue and was less potent at 5-HT1B receptor. These effects of J147 were blocked by pretreatment with a 5-HT1A antagonist NAD-299 and enhanced by a 5-HT1A agonist 8-OH-DPAT. However, 5-HT1B receptor antagonist NAS-181 did not appreciably alter the effects of J147 on depression-like behaviors. Moreover, pretreatment with NAD-299 blocked J147-induced increases in cAMP, PKA, pCREB, and BDNF expression in the hippocampus, while 8-OH-DPAT enhanced the effects of J147 on these proteins’ expression.Conclusion The results suggest that J147 induces rapid antidepressant-like effects during a 3-day treatment period without inducing drug tolerance. These effects might be mediated by 5-HT1A-dependent cAMP/PKA/pCREB/BDNF signaling.
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Objective Curcumin monoglucuronide (TBP1901) is highly water soluble and can convert to free form curcumin, which has pharmacological effects, on intravenous administration. This study aimed to investigate the effectiveness of TBP1901 intra-articular injections in an osteoarthritis (OA) rat model. Methods Sixty-four male Wistar rats (12 weeks old) who underwent destabilized medial meniscus (DMM) surgery were randomly separated into the TBP1901 injection or saline solution (control) injection group. They were sacrificed at 1, 2, 6, or 10 weeks postoperatively (weeks 1, 2, 6, and 10; n = 8 for each group). TBP1901 (30 mg/mL) or saline solution of 50 μL was injected into the knee joints twice a week during weeks 1 and 2 to investigate the effects in the acute phase of posttraumatic (PT) OA or once a week during weeks 6 and 10 to investigate it in the chronic phase of PTOA. Histology, immunohistochemistry, and micro-computed tomography were performed to evaluate the changes in OA. Results TBP1901 injections significantly reduced synovial inflammation at weeks 1 and 2, and tumor necrosis factor-α expression in the articular cartilage at week 6. The TBP1901 injections also significantly suppressed articular cartilage damage, subchondral bone (SB) plate thickening, SB plate perforation, and osteophyte formation at week 10. Conclusions TBP1901 intra-articular injections suppressed synovial inflammation in the acute phase of PTOA in DMM rats. In the chronic phase, TBP1901 suppresses articular cartilage damage and regulates SB plate changes.
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Background Current therapies for depression remain limited and plagued by various side effects. Problems associated with curcumin administration include poor aqueous solubility and bioavailability issues. Hence to overcome these, curcumin self micro emulsifying drug delivery system (SMEDDS) which will result in a nanosize emulsion droplets when administered in vivo were formulated in the present study. Methods Depression was induced by bilateral olfactory bulbectomy and the animals were randomized into 8 groups as normal, control [(vehicle 10 ml/kg, p.o., (per oral)], pure curcumin (10, 20, 40 mg/kg, p.o.), and curcumin SMEDDS (10, 20, 40 mg/kg, p.o). After 14 days of respective treatment, behavioral parameters such as open field test (OFT), ambulation counts and passive avoidance response (PAR) were evaluated. At the end of experiments, blood was withdrawn from r.o.p (retro orbital plexus) for serum cortisol estimation. Results In OFT, increased central area frequency, peripheral area frequency, central area duration and decreased rearing and grooming were recorded with an increased ambulation counts. In PAR, significant reduction in number of trials and step down from platform was observed in the animals treated with test drug. Serum cortisol level was also found to be decreased in the test groups. Conclusion Behavioral and biochemical estimations in the present study revealed the improved brain permeability and further increase in biological activity of curcumin SMEDDS.
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Objective: Methamphetamine (METH) increases dopamine, norepinephrine and serotonin concentrations in the synaptic cleft, and induces hyperactivity. The current management of acute METH poisoning relies on supportive care and no specific antidote is available for treatment. The main objective of this review was to present the evidence for effectiveness of the herbal medicine in alleviating the adverse effects of METH abuse. Materials and methods: Literature search was performed using the following electronic databases: MEDLINE, Scopus, PubMed and EMBASE. Results: Plant-derived natural products ginseng and sauchinone reduced METH-induced hyperactivity, conditioned place preference and neurological disorder. Garcinia kola decreased METH-induced hepatotoxicity, raised METH lethal dose, and restored the METH-impaired cognitive function. Repeated administration of baicalein resulted in attenuation of acute binge METH-induced amnesia via dopamine receptors. Activation of extracellular-regulated kinase in the hypothalamus by levo-tetrahydropalmatine facilitated the extinction of METH-induced conditioned place preference and reduced the hyperactivity. Other herbal medicine from various parts of the world were also discussed including hispidulin, silymarin, limonene, resveratrol, chlorogenic acid and barakol. Conclusion: Based on the current study, some natural products such as ginseng and levo-tetrahydropalmatine are promising candidates to treat METH abuse and poisoning. However, clinical trials are needed to confirm these finding.
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Depressive state adversely affects the memory functions, especially in the geriatric population. The initial stage of memory deficits associated with depression is particularly called as pseudodementia. It is the starting point of memory disturbance before dementia. The purpose of this research was to study depression and its consequent pseudodementia. For this purpose 24 male albino Wistar rats were divided into four groups. Depression was induced by 14 days of chronic restraint stress (CRS) daily for 4 h. After developing a depression model, pattern separation test was conducted to monitor pseudodementia in rats. Morris water maze test (MWM) was also performed to observe spatial memory. It was observed that model animals displayed impaired pattern separation and spatial memory. Treatment was started after the development of pseudodementia in rats. Curcumin at a dose of 200 mg/kg was given to model rats for one week along with the stress procedure. Following the treatment with curcumin, rats were again subjected to the aforementioned behavioral tests before decapitation. Corticosterone levels, brain derived neurotrophic factor (BDNF) and neurochemical analysis were conducted. Model rats showed depressogenic behavior and impaired memory performance. In addition to this, high corticosterone levels and decreased hippocampal BDNF, 5-HT, dopamine (DA), and acetylcholine (ACh) levels were also observed in depressed animals. These behavioral biochemical and neurochemical changes were effectively restored following treatment with curcumin. Hence, it is suggested from this study that pseudodementia can be reversed unlike true dementia by controlling the factors such as depression which induce memory impairment.
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Major depressive disorder (MDD) is one of the most prevalent and debilitating disorders. Current available treatments are somehow limited, so alternative therapeutic approaches targeting different biological pathways are being investigated to improve treatment outcomes. Curcumin is the main active component in the spice turmeric that has been used for centuries in Ayurvedic medicine to treat a variety of conditions, including anxiety and depressive disorders. In the past decades, curcumin has drawn researchers' attention and displays a broad range of properties that seem relevant to depression pathophysiology. In this review, we break down the potential mechanisms of action of curcumin with emphasis on the diverse systems that can be disrupted in MDD. Curcumin has displayed, in a number of studies, a potency in modulating neurotransmitter concentrations, inflammatory pathways, excitotoxicity, neuroplasticity, hypothalamic–pituitary–adrenal disturbances, insulin resistance, oxidative and nitrosative stress, and endocannabinoid system, all of which can be involved in MDD pathophysiology. To date, a handful of clinical trials have been published and suggest a benefit of curcumin in MDD. With evidence that is progressively growing, curcumin appears as a promising alternative option in the management of MDD.
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Medicinal plants and their extracts are natural remedies with enormous potential for treating various diseases, including depression and anxiety. In the case of depression, hundreds of plants have traditionally been used in folk medicine for generations. Different plant extracts and natural products have been analyzed as potential antidepressant agents with validated models to test for antidepressant-like effects in animals, although other complementary studies have also been employed. Most of these studies focus on the possible mediators implicated in these potential effects, with dopamine, serotonin, and noradrenaline being the principal neurotransmitters implicated, both through interference with receptors and with their metabolism by monoamino oxidases, as well as through neuro-endocrine and neuroprotective effects. There are approximately 650 reports of antidepressant-like medicinal plants in PubMed; 155 of them have been compiled in this review, with a relevant group yielding positive results. Saffron and turmeric are the most relevant species studied in both preclinical and clinical studies; St. Johnʼs wort or kava have also been tested extensively. To the best of our knowledge, no review to date has provided a comprehensive understanding of the biomolecular mechanisms of action of these herbs or of whether their potential effects could have real benefits. The purpose of this narrative review is to provide an update regarding medicinal plants from the year 2000 to the present to examine the therapeutic potential of these antidepressant-like plants in order to contribute to the development of new therapeutic methods to alleviate the tremendous burden that depression causes worldwide.
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Curcuma longa is a plant that belongs to the ginger family, Zingiberaceae. It has been used in Siddha medicine for thousands of years in Asia. Parkinson's disease (PD) is a degenerative disorder of the central nervous system that affects the motor system of the brain. Death of dopamine-producing cells in the substantia nigra leads to PD. Exposure to salsolinol, which is an endogenous neurotoxin, has been associated with damage to dopamine-producing cells. The present study assessed the toxicity of salsolinol in SH-SY5Y human neuroblastoma cells and subsequently investigated the neuroprotective potential of C. longa extract in salsolinol-induced toxic conditions in SH-SY5Y cells. Sulphorhodamine-B assay showed the protective effect of the anti-apoptotic effect of treated SH-SY5Y cells. Fluorescence microscopy and confocal laser scanning microscope analysis indicated the anti-apoptotic impact of the C. longa extract. Mitochondria-derived reactive oxygen species were reduced in C. longa extract-treated SH-SY5Y cells. Downregulated mRNA expression levels of p53, Bcl-2-associated X protein and caspase 3 were observed in the C. longa extract-treated SH-SY5Y cells. Caspase 3 activity was reduced in the C. longa extract-treated SH-SY5Y cells. In conclusion, the present findings demonstrated that solsolinol is neurotoxic to SH-SY5Y cells, and C. longa extract may be useful in the treatment of PD.
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Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.
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Effect of feeding 0.5% curcumin diet or 1% cholesterol diet was examined in albino rats rendered diabetic with streptozotocin injection. Diabetic rats maintained on curcumin diet for 8 weeks excreted comparatively less amounts of albumin, urea, creatinine and inorganic phosphorus. Urinary excretion of the electrolytes sodium and potassium were also significantly lowered under curcumin treatment. Dietary curcumin also partially reversed the abnormalities in plasma albumin, urea, creatine and inorganic phosphorus in diabetic animals. On the other hand, glucose excretion or the fasting sugar level was unaffected by dietary curcumin and so also the body weights were not improved to any significant extent. Diabetic rats fed curcumin diet had a lowered relative liver weight at the end of the study compared to other diabetic groups. Diabetic rats fed a curcumin diet also showed lowered lipid peroxidation in plasma and urine when compared to other diabetic groups. The extent of lipid peroxidation on the other hand, was still higher in cholesterol fed diabetic groups compared to diabetic rats fed with control diet. Thus, the study reveals that curcumin feeding improves the metabolic status in diabetic conditions, despite no effect on hyperglycemic status or the body weights. The mechanism by which curcumin improves this situation is probably by virtue of its hypocholesterolemic influence, antioxidant nature and free radical scavenging property.
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Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.
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The pathophysiology of major affective illness is poorly understood. However, several lines of preclinical and clinical evidence indicate that an enhancement of 5-HT-mediated neurotransmission might underlie the therapeutic effect of most antidepressant treatments. This net effect would, however, be obtained via different mechanisms. A better understanding of the neurobiological basis for the delayed onset of action of antidepressant treatments has led to the elaboration of strategies that could accelerate the antidepressant response. These strategies are discussed in this article by Pierre Blier and Claude de Montigny.
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In this paper we present a comparison of the Two-Poisson (2P), Inverse Document Frequency (IDF) and Discrimination Value (DV) models of document representation. The first objective of the study was to understand the nature of the relationship between the term property underlying the 2P model and the other statistical properties of index terms that we known about: discrimination value and inverse document frequency. The second objective was to compare the properties with respect to the feature of ultimate interest, i.e., retrieval effectiveness. The study showed that 2P and IDF properties work in parallel, while 2P and DV have a negative relationship. An explanation for this negative correlation was given by viewing the distribution of inter document dissimilarities. In the retrieval experiment most of the 2P strategies tested acheived the same performance level as the DV and IDF strategies. The important conclusion made from this study is that despite the fact that the 2P model is extremely selective in its choice of indexing vocabulary for a database, it still performs with the same effectiveness as the more traditional models. The overall contribution of this work is in the area of understanding features that influence the indexing potential of terms.
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An extract of the crude drug "ukon", the rhizomes of CURCUMA LONGA, exhibited intense preventive activity against carbon tetrachloride-induced liver injury IN VIVO and IN VITRO. The extract was subjected to fractionation by monitoring the activity by the IN VITRO assay methods employing carbon tetrachloride- and galactosamine-produced cytotoxicity in primary cultured rat hepatocytes. Curcuminoids were shown to possess significant antihepatotoxic action. The liver protective effects of some analogues of ferulic acid and p-coumaric acid, probable metabolites of the curcuminoids, were also evaluated.
Article
In control rats small doses of apomorphine (25 to 100 μg/kg) decreased motor activity and reduced DOPAC content in the caudate nucleus. A larger dose (500 μg/kg) increased motor activity and elicited stereotypy. Chronic treatment with imipramine, amitryptiline and mianserine (10, 10 and 2.5 mg/kg twice daily for 10 days respectively) counteracted or reversed the effect of small doses of apomorphine on motor activity, left DOPAC content unchanged and potentiated the central stimulant response to the larger dose of apomorphine. Changes in apomorphine responses were observed after ten but not after two days of imipramine treatment and persisted unaltered up to 4 days after imipramine withdrawal. It is suggested that chronic treatment with antidepressants induces persistent subsensitivity in presynaptic dopamine receptors. The relevance of the findings in the therapeutic effect of these drugs is discussed.
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Rats and mice when forced to swim in a restricted space will rapidly cease attempts to escape and become immobile. Previous experiments have shown that immobility was selectively reduced by antidepressant agents. The present experiments show that important differences exist between strains in both the amount of immobility observed and the effects of imipramine. Strain differences should therefore be taken into account in attempts to replicate results from one laboratory to another.
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The data reviewed indicate that extracts of Curcuma longa exhibit anti-inflammatory activity after parenteral application in standard animal models used for testing anti-inflammatory activity. It turned out that curcumin and the volatile oil are at least in part responsible for this action. It appears that when given orally, curcumin is far less active than after i.p. administration. This may be due to poor absorption, as discussed. Data on histamine-induced ulcers are controversial, and studies on the secretory activity (HCl, pepsinogen) are still lacking. In vitro, curcumin exhibited antispasmodic activity. Since there was a protective effect of extracts of Curcuma longa on the liver and a stimulation of bile secretion in animals, Curcuma longa has been advocated for use in liver disorders. Evidence for an effect on liver disease in humans is not yet available. From the facts that after oral application only traces of curcumin were found in the blood and that, on the other hand, most of the curcumin is excreted via the faeces it may be concluded that curcumin is absorbed poorly by the gastrointestinal tract and/or underlies pre-systemic transformation. Systemic effects therefore seem to be questionable after oral application except that they occur at very low concentrations of curcumin. This does not exclude a local action in the gastrointestinal tract.
Article
In the forced swimming-induced immobility (despair) test model, adenosine, and 2-chloroadenosine treatment prolonged the immobilization period in mice. Dipyridamole, which is known to inhibit adenosine uptake, potentiated the adenosine effect. The purinoceptor antagonists caffeine and theophylline blocked purine nucleoside-induced enhancement of immobilization. Tricyclic antidepressants such as imipramine and desipramine, the MAO inhibitor tranylcypromine, and amphetamine, a psychostimulant, reversed purine nucleoside-induced immobility. On the other hand, quipazine, fluoxetine, and amitriptyline failed to reverse purine nucleosides-induced prolongation of immobility. None of the antidepressants in the doses investigated had any effect by themselves. Reserpine also prolonged forced swimming-induced immobility in mice. The antidepressants fluoxetine and quipazine, but not methylxanthine pretreatment, reversed reserpine-induced immobility in this test model. These results indicate that adenosine and 2-chloroadenosine probably reduce norepinephrine outflow through their action on presynaptic purinoceptors on noradrenergic neurons and thereby cause prolongation of immobility in animals.
Article
L-Arginine-derived nitric oxide (NO) and its derivatives, such as peroxynitrite and nitrogen dioxide, play a role in inflammation and also possibly in the multistage process of carcinogenesis. We investigated the effect of various non-steroidal anti-inflammatory agents and related compounds on the induction of NO synthase (NOS) in RAW 264.7 macrophages activated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Low concentrations of curcumin, a potent anti-tumour agent having anti-inflammatory and anti-oxidant properties, inhibited NO production, as measured by the amount of nitrite released into the culture medium in 24 h (IC50 = 6 microM). NOS activity in soluble extracts of macrophages activated for 6-24 h in the presence of curcumin (10 microM) was significantly lower than that of macrophages activated without curcumin. Northern-blot and immunoblotting analyses demonstrated that significantly reduced levels of the mRNA and 130-kDa protein of inducible NOS were expressed in macrophages activated with curcumin, compared to those without curcumin. Inhibition of NOS induction was maximal when curcumin was added together with LPS and IFN-gamma and decreased progressively as the interval between curcumin and LPS/IFN-gamma was increased to 18 h.
Article
Earlier studies showed that curcumin is a potent inhibitor iron-catalysed lipid peroxidation. Demethoxycurcumin, bisdemethoxycurcumin and acetylcurcumin were tested for their ability to inhibit iron-stimulated lipid peroxidation in rat brain homogenate and rat liver microsomes. Comparison of the results with curcumin showed that all compounds are equally active, and more potent than alpha-tocopherol. These results showed that the methoxy and phenolic groups contribute little to the activity. Spectral studies showed that all compounds could interact with iron. Thus, the inhibition of iron-catalysed lipid peroxidation by curcuminoids may involve chelation of iron.
Article
Effect of myocardial ischaemia on the bioantioxidants levels in the cat heart was evaluated. In addition, effect of curcumin, an anti-inflammatory and anti-thrombotic drug, and quinidine, a standard antiarrhythmic drug, was also studied in the cat. Myocardial ischaemia was induced by the ligation of left descending coronary artery. Quinidine (1 mg/kg, iv) was administered 15 min prior to while curcumin (100 mg/kg, ip) was given 30 min before ligation. Hearts were removed 4 h post coronary artery ligation. Levels of glutathione (GSH), malonaldelhyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT) and lactate dehydrogenase (LDH) were estimated in the ischaemic and non-ischaemic zones. Both the drugs protected the animals against decrease in the heart rate and blood pressure following ischaemia. In the ischaemic zone, after 4 h of ligation, an increase in the level of MDA and activities of MPO and SOD (cytosolic fraction) were observed. Quinidine and curcumin pretreatment prevented the ischaemia-induced elevation in MDA contents and LDH release. Curcumin pretreatment did not prevent the increase in MPO activity while quinidine did. Results obtained indicate alterations in the bioantioxidants following ischaemia and both curcumin and quinidine prevented ischaemia induced changes in the cat heart.
Article
Laboratory animal model studies have suggested that curcumin may play an important role in inhibiting the process of carcinogenesis. Curcumin, the yellow pigment that is obtained from rhizomes of the plant Curcuma longa Linn (Family Zingiberaceae), is commonly used as a spice and food coloring agent. The present study was designed to investigate the chemopreventive action of dietary curcumin on 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in male Swiss ablino mice. At 6 weeks of age, groups of animals were fed the standard (modified AIN-76 A) diet or a diet containing 1% curcumin. At 8 weeks of age, all animals, except those in the vehicle (acetone)-treated groups, received 100 microg of DMBA dissolved in 100 microl of acetone in a single application to the skin of the back. From 1 week after DMBA application, tumor promoter (2.5 microg of TPA dissolved in 100 microl of acetone) was applied to the same areas on mouse skin twice a week for 26 weeks. All groups continued on their respective dietary regimen until the termination of the experiment. The results indicate that dietary administration of curcumin significantly inhibited the number of tumors per mouse (P < 0.05) and the tumor volume (P < 0.01). The percentage of tumor-bearing mice tended to be lower in the mice on the curcumin diet than those on the standard diet. There was no difference in growth between mice of the standard and 1% curcumin groups. The results indicate the safety and the anti-carcinogenic effect of curcumin in mice.
Article
The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.
Article
Glial cell monoamine oxidase (MAO) activity has been implicated as a contributor to oxidative neuronal damage associated with various neurodegenerative diseases. The attenuation of MAO activity may provide protection against oxidative neurodegeneration. In this investigation, the presence of MAO-B in rat C6 astrocyte cells was substantiated by dose-dependent inhibition of enzyme activity in the presence of chlorgyline-HCl and L-deprenyl. The present study evaluated various dietary-derived food constituents for evidence of inhibition on oxidative deamination of monoamines or peroxide radical trapping capacity. Results of this investigation indicate that compounds which inhibit C6 glial cell MAO enzyme activity or scavenge peroxide product include chlorogenic acid, (+)-catechin, taxifolin, (-)-epigallocatechin gallate (EGCG), fisetin, coenzyme Q0, curcumin, sesamol, morin, sesame oil, silymarin, green tea, ferulic acid, caffeic acid, and rutin hydrate. The results of this study indicate that dietary compounds can attenuate peroxide production in glial cells by either inhibiting the deamination of monoamines or acting as a free radical scavenger.
Article
The dichloromethane fraction from Areca catechu was found to inhibit monoamine oxidase type A isolated from the rat brain with an IC50 of 665 +/- 65.1 microg/ml. Studies with pharmacological models of depression, i.e., forced swim and tail-suspension tests, indicated that it caused significant reduction in the immobility time similar to that of moclobemide (a selective inhibitor of MAO-A) without causing a significant change in motor performance. Alkaloids such as arecaidine, arecoline, and a few other constituents, reported to be present in Areca catechu were also tested, but none of them were found to inhibit MAO. Present study suggests that the dichloromethane fraction from A. catechu possesses antidepressant property via MAO-A inhibition.
Article
In the traditional system of medicine, Ayurveda, several spices and herbs are thought to possess medicinal properties. Among the spices, turmeric rhizomes (Curcuma longa. Linn.) are used as flavoring and coloring agents in the Indian diet everyday. In this research, we studied the effect of turmeric and its active principle, curcumin, on diabetes mellitus in a rat model. Alloxan was used to induce diabetes. Administration of turmeric or curcumin to diabetic rats reduced the blood sugar, Hb and glycosylated hemoglobin levels significantly. Turmeric and curcumin supplementation also reduced the oxidative stress encountered by the diabetic rats. This was demonstrated by the lower levels of TBARS (thiobarbituric acid reactive substances), which may have been due to the decreased influx of glucose into the polyol pathway leading to an increased NADPH/NADP ratio and elevated activity of the potent antioxdiant enzyme GPx. Moreover, the activity of SDH (sorbitol dehydrogenase), which catalyzes the conversion of sorbitol to fructose, was lowered significantly on treatment with turmeric or curcumin. These results also appeared to reveal that curcumin was more effective in attenuating diabetes mellitus related changes than turmeric.
Article
Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide variety of physiological functions by activating multiple receptors, and abnormalities of these receptor systems has been implicated in many psychiatric disorders including anxiety, depression, psychosis, migraine, disorders of sexual functioning, sleep, cognition, and feeding. Many of the currently used treatments for these disorders act by affecting the serotonergic system. Observation of serotonin receptor alterations, before and following effective treatments, may yield important insights into the aetiology of these psychiatric disorders and may ultimately lead to more selective and effective therapies. Copyright 2000 John Wiley & Sons, Ltd.
Article
The present study employed in-vivo microdialysis techniques in the freely moving rat to systematically compare the neurochemical effects of various antidepressant agents on extracellular concentrations of norepinephrine (NE) and serotonin (5-HT) in the frontal cortex. We found that acute administration of the tricyclic antidepressant, desipramine (3-30 mg/kg, s.c.) and the dual serotonin/norepinephrine reuptake inhibitor, venlafaxine (3-30 mg/kg, s.c.), produced dose-dependent and robust increases in cortical NE concentrations (498% and 403%, respectively). Conversely, acute injection of the selective serotonin reuptake inhibitors, fluoxetine (30 mg/kg, s.c.) and paroxetine (1-10 mg/kg, s.c.), did not alter forebrain NE concentrations. However, paroxetine did produce a significant increase in cortical NE concentrations (164%) when administered at 30 mg/kg. These changes in NE were not paralleled by 5-HT, which showed no increase following administration of desipramine, venlafaxine, paroxetine or fluoxetine. Combination treatment with the 5-HT1A receptor antagonist, WAY-100635 (0.3 mg/kg, s.c.), significantly enhanced extracellular 5-HT concentrations following venlafaxine (10 and 30 mg/kg), fluoxetine (30 mg/kg) and paroxetine (3-30 mg/kg). Alternatively, WAY-100635 produced no augmentation of the antidepressant-induced changes in extracellular NE. Collectively, these studies show that paroxetine, at low to intermediate doses, and fluoxetine are selective for 5-HT versus NE systems, whereas venlafaxine produces similar effects on both 5-HT and NE levels at the effective doses tested.
Article
Depressive disorders are among the most frequent psychiatric diseases in the Western world with prevalence numbers between 9% and 18%. They are characterized by depressed mood, a diminished interest in pleasurable activities, feelings of worthlessness or inappropriate guilt, decrease in appetite and libido, insomnia, and recurrent thoughts of death or suicide. Among other findings, reduced activity of monoaminergic neurotransmission has been postulated to play a role in the pathogenesis of depression. Consistent with this hypothesis, most antidepressive drugs exert their action by elevating the concentration of monoamines in the synaptic cleft. However, it is not the enhancement of monoaminergic signaling per se, but rather long-term, adaptive changes that may underlie the therapeutic effect. These include functional and structural changes that are discussed later. In addition, in the last years, evidence has emerged that remissions induced in patients using lithium or electroconvulsive therapy are accompanied by structural changes in neuronal networks thereby affecting synaptic plasticity in various regions of the brain.
Article
The role of the monoamines serotonin and noradrenaline in mental illnesses including depression is well recognized. All antidepressant drugs in clinical use increase acutely the availability of these monoamines at the synapse either by inhibiting their neuronal reuptake, inhibiting their intraneuronal metabolism, or increasing their release by blocking the alpha(2) auto- and heteroreceptors on the monoaminergic neuron. This acute increase in the amount of the monoamines at the synapse has been found to induce long-term adaptive changes in the monoamine systems that end up in the desensitization of the inhibitory auto- and heteroreceptors including the presynaptic alpha(2) and 5-HT(1B) receptors and the somatodendritic 5-HT(1A) receptors located in certain brain regions. The desensitization of these inhibitory receptors would result in higher central monoaminergic activity that coincides with the appearance of the therapeutic response. These adaptive changes responsible for the therapeutic effect depend on the availability of the specific monoamine at the synapse, as depletion of the monoamines will either reverse the antidepressant effect or causes a relapse in the state of drug-free depressed patient previously treated with antidepressant drugs. Furthermore, blocking the somatodendritic 5-HT(1A) or nerve terminal alpha(2) receptors proved to increase the response rate in the treatment of major and treatment-resistant depression, providing further support to the assumption that the antidepressant effect results from the long-term adaptive changes in the monoamine auto- and heteroregulatory receptors. On the other hand, the chronic treatment with antidepressants resulted in D(2) receptors supersensitivity in the nucleus accumbens. This supersensitivity might play a role in the mechanisms underlying antidepressant induced mood switch and rapid cycling.
Article
Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used effectively to treat depression-related diseases in China. There is no information available about the antidepressant activity of curcumin, the active component of curcuma longa. In the present study, we analyzed the effects of curcumin on depressive-like behaviors in mice, using two animal models of depression. Our results showed that curcumin treatment at 5 and 10 mg/kg (p.o.) significantly reduced the duration of immobility in both the tail suspension and forced swimming tests. These doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical assays showed that curcumin produced a marked increase of serotonin and noradrenaline levels at 10 mg/kg in both the frontal cortex and hippocampus. Dopamine levels were also increased in the frontal cortex and the striatum. Moreover, curcumin was found to inhibit monoamine oxidase activity in the mouse brain. These findings suggest that the antidepressant-like effects of curcumin may involve the central monoaminergic neurotransmitter systems.
Article
Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and we hypothesized that curcumin would have an influence on depressive-like behaviors. The purpose of the present study was to confirm the putative antidepressant effect of chronic administrations of curcumin (1.25, 2.5, 5 and 10 mg/kg, p.o.) in the forced swimming test and bilateral olfactory bulbectomy (OB) models of depression in rats. In the first study, chronic treatment with curcumin (14 days) reduced the immobility time in the forced swimming test. In the second experiment, curcumin reversed the OB-induced behavioral abnormalities such as hyperactivity in the open field, as well as deficits in step-down passive avoidance. In addition, OB-induced low levels of serotonin (5-HT), noradrenaline (NA), high 5-hydroxyindoleacetic acid (5-HIAA) and 4-dihydroxyphenylacetic acid (DOPAC) in the hippocampus were observed, and were completely reversed by curcumin administration. A slight decrease in 5-HT, NA and dopamine (DA) levels was found in the frontal cortex of OB rats which was also reversed by curcumin treatment. These results confirm the antidepressant effects of curcumin in the forced swim and the OB models of depression in rats, and suggest that these antidepressant effects may be mediated by actions in the central monoaminergic neurotransmitter systems.
Article
Cyclooxygenase (COX) is reported to play a significant role in neurodegeneration. Recent studies have shown that chronic ethanol administration up-regulates cyclooxygenase expression. In the present study we examined the effect of nimesulide (a preferential COX-2 inhibitor), rofecoxib (a highly selective COX-2 inhibitor) or naproxen (a non-selective COX-inhibitor displaying high affinity towards the COX-1 isoenzyme) on alcohol-induced withdrawal symptoms. Mice were made physically dependent on alcohol by the chronic administration of ethanol (2 g/kg of 10% v/v), intragastrically, twice on day 1 and then once-daily on successive days for a total of 7 days. Nimesulide [2.5 mg/kg, intraperitoneally (i.p.)], rofecoxib (2 mg/kg, i.p.) or naproxen (7 mg/kg, i.p.) were administered daily for 7 days before administering alcohol intragastrically. After 24 hours of the last alcohol administration, the treatments were reversed and the mice were tested for withdrawal, so that the animals that had received COX-inhibitors followed 30 minutes later by ethanol on days 1-7 were challenged with saline. Similarly, the animals which received saline followed 30 minutes later by ethanol received only saline. Behavioural analysis revealed hyperlocomotor activity, increased anxious response and increased hyperalgesia in mice. Also, alcohol withdrawal decreased the threshold for Pentylenetetrazole-(PTZ)-induced convulsions. Pretreatment with COX-inhibitors rofecoxib (2 mg/kg, i.p.) or nimesulide (2.5 mg/kg, i.p.) displayed significant protection against ethanol-induced withdrawal symptoms, while naproxen (7 mg/kg, i.p.) was not effective in reversing alcohol-induced withdrawal symptoms. The results of the present study suggest strongly the possible role of cyclooxygenases, particularly COX-2 inhibitors, on ethanol-induced withdrawal symptoms and the potential use of COX-2 inhibitors in their prevention and treatment.
Article
The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED(50) values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.
Article
Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least in part, an interaction with 5-HT(1A/1B) and 5-HT(2C) receptors.
The antidepressant effects of curcumin in the forced swimming test involve 5-HT 1 and 5-HT 2 receptors
  • R Y Xu
  • Wu
  • Hl
  • Li
  • Li Yh Yb
  • Guo
  • Jb
  • Li
  • Xj
R, Xu Y, Wu HL, Li YB, Li YH, Guo JB, Li XJ (2008) The antidepressant effects of curcumin in the forced swimming test involve 5-HT 1 and 5-HT 2 receptors. Eur J Pharmacol 578(1):43–50
A review of the role of serotonin receptors in psychiatric disorders Behavioural despair in rats and mice: strain differences and the effects of imipramine
  • M Mulrooney
  • Jb
  • Leonard
  • Porsolt Rd
  • A Bertin
  • Jalfre
M, Mulrooney JB, Leonard BE (2000) A review of the role of serotonin receptors in psychiatric disorders. Hum Psychophar-macol Clin Exp 15:397–415 Porsolt RD, Bertin A, Jalfre M (1978) Behavioural despair in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol 51:291–294
Dose escalation of a curcuminoid formulation
  • Cd
  • Ruffin
  • th
  • D Normolle
  • Heath
  • Dd
  • Murray
  • Bailey Jm Si
  • Boggs Me J Crowell
  • Rock Cl Brenner
  • De
CD, Ruffin MT 4th, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE (2006) Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 6:10
Purine nucleoside-mediated immo-bility in mice: reversal by antidepressants
  • Sk
  • Mehta
SK, Mehta AK (1985) Purine nucleoside-mediated immo-bility in mice: reversal by antidepressants. Psychopharmacology (Berl) 85(4):460–463
New insights into the mechanisms of antidepressant therapy
  • P Henm
  • Fa
P, Henm FA (2004) New insights into the mechanisms of antidepressant therapy. Pharmacol Ther 102:47–60
Pharmacology of Curcuma longa
  • H P Ammon
  • M A Wahl
  • HP Ammon
Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound
  • C V Rao
  • A Rivenson
  • B Simi
  • CV Rao