Ying Xu

Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats

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.

Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats

Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. As the active component of curcuma longa, curcumin possesses many therapeutic properties; we have previously described its antidepressant activity in our earlier studies using the chronic unpredictable stress model of depression in rats. Recent studies show that stress-induced damage to hippocampal neurons may contribute to the phathophysiology of depression. The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT(1A) mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT(1A) receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin.

Antidepressant-like effect of trans-resveratrol: Involvement of serotonin and noradrenaline system.

The antidepressant-like effect of trans-resveratrol, a phenolic compound present in polygonum cuspidatum, was evaluated through behavioral and neurochemical methods. trans-Resveratrol (20, 40 and 80 mg/kg, via gavage) significantly decreased the immobility time in mouse models of despair tests, but did not influence locomotor activity. Two behavioral models and neurochemical assays suggested that trans-resveratrol produced a significant increase in serotonin and noradrenaline levels at 40 or 80 mg/kg in brain regions. In addition, trans-resveratrol dose dependently inhibited MAO-A activity. These findings indicate that the antidepressant-like effect of trans-resveratrol might be related to serotonergic and noradrenergic activation.

Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress

Chronic stress occurs in everyday life and induces impaired spatial cognition, neuroendocrine and plasticity abnormalities. A potential therapeutic for these stress related disturbances is curcumin, derived from the curry spice turmeric. Previously we demonstrated that curcumin reversed the chronic stress-induced behavioral deficits in escape from an aversive stimulus, however the mechanism behind its beneficial effects on stress-induced learning defects and associated pathologies are unknown. This study investigated the effects of curcumin on restraint stress-induced spatial learning and memory dysfunction in a water maze task and on measures related neuroendocrine and plasticity changes. The results showed that memory deficits were reversed with curcumin in a dose dependent manner, as were stress-induced increases in serum corticosterone levels. These effects were similar to positive antidepressant imipramine. Additionally, curcumin prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus, as assessed by the changes in branch points and dendritic length. In primary hippocampal neurons it was shown that curcumin or imipramine protected hippocampal neurons against corticosterone-induced toxicity. Furthermore, the portion of calcium/calmodulin kinase II (CaMKII) that is activated (phosphorylated CaMKII, pCaMKII), and the glutamate receptor sub-type (NMDA(2B)) expressions were increased in the presence of corticosterone. These effects were also blocked by curcumin or imipramine treatment. Thus, curcumin may be an effective therapeutic for learning and memory disturbances as was seen within these stress models, and its neuroprotective effect was mediated in part by normalizing the corticosterone response, resulting in down-regulating of the pCaMKII and glutamate receptor levels.

Gene expression in the hippocampus: Regionally specific effects of aging and caloric restriction

We measured changes in gene expression, induced by aging and caloric restriction (CR), in three hippocampal subregions. When analysis included all regions, aging was associated with expression of genes linked to mitochondrial dysfunction, inflammation, and stress responses, and in some cases, expression was reversed by CR. An age-related increase in ubiquintination was observed, including increased expression of ubiquitin conjugating enzyme genes and cytosolic ubiquitin immunoreactivity. CR decreased cytosolic ubiquitin and upregulated deubiquitinating genes. Region specific analyses indicated that CA1 was more susceptible to aging stress, exhibiting a greater number of altered genes relative to CA3 and the dentate gyrus (DG), and an enrichment of genes related to the immune response and apoptosis. CA3 and the DG were more responsive to CR, exhibiting marked changes in the total number of genes across diet conditions, reversal of age-related changes in p53 signaling, glucocorticoid receptor signaling, and enrichment of genes related to cell survival and neurotrophic signaling. Finally, CR differentially influenced genes for synaptic plasticity in CA1 and CA3. It is concluded that regional disparity in response to aging and CR relates to differences in vulnerability to stressors, the availability of neurotrophic, and cell survival mechanisms, and differences in cell function.

Antidepressant-like effect of low molecular proanthocyanidin in mice: Involvement of monoaminergic system

Proanthocyanidin is a phenolic product present in plants which has antioxidant, antinociceptive and neuroprotective properties, without inducing significant toxicological effects. The present study tested the hypothesis that low molecular proanthocyanidin from grapes that has optimized bioavailability, would exert antidepressant-like activities in behavioral despair tests. The results suggested that oral administration proanthocyanidin at doses of 25 and 50mg/kg for 7days significantly reduced the duration of immobility in both the tail suspension and forced swimming tests. The doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical and neuropharmacological assays showed that proanthocyanidin produced a marked increase of 5-HT levels at 25 and 50mg/kg in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased when higher dose of proanthocyanidin (50mg/kg) administration both in the frontal cortex and hippocampus. These effects were similar to those observed for the classical antidepressant imipramine (10mg/kg, i.p.). Moreover, Our study suggested that proanthocyanidin (12.5, 25 and 50mg/kg) dose dependently inhibited monoamine oxidase-A (MAO-A) activity, while MAO-B inhibitory activity was also found at higher doses (25 and 50mg/kg) after 7days administration. MAO-A selective inhibitor, moclobemide (20mg/kg, i.g.) produced MAO-A inhibition of 70.5% in the mouse brain. These findings suggest that the antidepressant-like effects of proanthocyanidin may involve the central monoaminergic neurotransmitter systems.

Corticosterone induced morphological changes of hippocampal and amygdaloid cell lines are dependent on 5-HT7 receptor related signal pathway

Stress is an unavoidable life experience. It induces mood, cognitive dysfunction and plasticity changes in chronically stressed individuals. Among the various brain regions that have been studied, the hippocampus and amygdala have been observed to have different roles in controlling the limbic-hypothalamic-pituitary-adrenal axis (limbic-HPA axis). This study investigated how the stress hormone corticosterone (CORT) affects neuronal cells. The first aim is to test whether administration of CORT to hippocampal and amygdaloid cell lines induces different changes in the 5-HT receptor subtypes. The second goal is to determine whether stress induced morphological changes in these two cell lines were involved in the 5-HT receptor subtypes expression. We now show that 5-HT(7) receptor mRNA levels were significantly upregulated in HT-22 cells, but downregulated in AR-5 cells by exposure to a physiologically relevant level of CORT (50 μM) for 24 h, which was later confirmed by primary hippocampal and amygdaloid neuron cultures. Additionally, pretreatment of cells with 5-HT(7) antagonist SB-269970 or agonist LP-44 reversed CORT induced cell lesion in a dose-dependent manner. Moreover, CORT induced different changes in neurite length, number of neurites and soma size in HT-22 and AR-5 cells were also reversed by pretreatment with either SB-269970 or LP-44. The different effects of 5-HT(7) receptors on cell lines were observed in two members of the Rho family small GTPase expression: the Cdc-42 and RhoA. These observed results support the hypothesis that 5-HT may differentially modulate neuronal morphology in the hippocampus and amygdala depending on the expression levels of the 5-HT receptor subtypes during stress hormone insults.

Curcumin prevents corticosterone-induced neurotoxicity and abnormalities of neuroplasticity via 5-HT receptor pathway.

J. Neurochem. (2011) 118, 784–795.

Animal Models of Depression and Neuroplasticity: Assessing Drug Action in Relation to Behavior and Neurogenesis

Depression is among the most prevalent forms of mental illness and a major cause of morbidity worldwide. Diagnosis of depression is mainly based on symptomatic criteria, and the heterogeneity of the disease suggests that multiple different biological mechanisms may underlie its etiology. Animal models have been important for recent advances in experimental neuroscience, including modeling of human mood disorders, such as depression and anxiety. Over the past few decades, a number of stress and neurobiochemical models have been developed as primary efficacy measures in depression trials, which are paving the way for the discovery of novel therapeutic targets. Recent data indicates that stress-related mood disorders have influence on neuroplasticity and adult neurogenesis. In this chapter, several currently available animal models are presented as powerful tools for both mechanistic studies into the neurobiology of the antidepressant response and for drug discovery.

The Serotonergic System and Neuroplasticity are Implicated in the Effect of Phytochemicals on Mood and Cognitive Disorders

Studies has been established in the 1930s that any environmental changes, whether internal or external, that disturbs the maintenance of homeostasis can cause stress response, including psychological, neuronal, endocrine and immune system reactivity (B E Leonard, 2005). During chronic stress or long-term exposure to external stress, glucocorticosteroids induce the hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis, which produces an increase in plasma glucocorticoid level that then impairs the negative feedback mechanism, causing psychological disorders (Croes, Merz, & Netter, 1993; Henry, 1992). In stress-induced emotional and cognitive disorders, such as depression, anxiety and learning and memory impairment, the serotonergic system mainly exerts its regulatory functions through different subtypes of receptors. Research over the past decades have found that serotonin receptors, such as 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT4, 5-HT6, and 5-HT7 subtypes, are closely related to depression and memory deficits. Moreover, clinical investigation suggests that some of the agonists or antagonists of the 5-HT receptor subtypes can be used for treatment of depression. However, the detailed roles of serotonin receptors in these disorders remain unclear. Neuroplasticity has been described as the ability of the brain to reorganize itself and form new neuronal connections throughout life. Depression is associated with a neuronal loss in specific brain regions, which has been proven by functional brain imaging and other neurobiological techniques. The dendritic abnormalities seen in the hippocampus in animal models of depression and in patients with depression and Alzheimer’s suggest changes in hippocampal circuitry are involved in disorders involving depression, anxiety and learning and memory impairment. The morphological and functional changes of neurons may be reversed after treatment with antidepressants, such as some natural compounds. In this review, a connection between neuroplasticity and the antidepressant-like effects of phytochemicals that are currently being studied is brought into attention. Some phytochemicals, such as curcumin, are found to reverse impaired hippocampal