Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate NMDA receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of AMPA receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5–5.0 mg/kg ip) and chronically (0.5–2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in the FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression.

Rationale A number of preclinical and clinical studies suggest ketamine, a glutamate NMDA (N-methyl-D-aspartate) receptor antagonist, has a rapid and lasting antidepressant effect when administered either acutely or chronically. It has been postulated that this effect is due to stimulation of AMPA (alpha-amino-3-hydroxy-5-methyl–4-isoxazolepropionic acid) receptors. Objective In this study, we tested whether AMPA alone has an antidepressant effect and if the combination of AMPA and ketamine provides added benefit in Wistar-Kyoto (WKY) rats, a putative animal model of depression. Results Chronic AMPA treatment resulted in a dose dependent antidepressant effect in both the forced swim test (FST) and sucrose preference test. Moreover, chronic administration (10–11d) of combinations of AMPA and ketamine, at doses that were ineffective on their own, resulted in a significant antidepressant effect. The behavioral effects were associated with increases in hippocampal brain derived neurotrophic factor (BDNF), synapsin, and mammalian target of rapamycin (mTOR). Conclusion These findings are the first to provide evidence for an antidepressant effect of AMPA, and suggest the usefulness of AMPA-ketamine combination in treatment of depression. Furthermore, these effects appear to be associated with increases in markers of hippocampal neurogenesis and synaptogenesis, suggesting a mechanism of their action.

Resveratrol (3,4’,5-trihydroxy-trans-stilbene) is a natural non-flavonoid polyphenol antioxidant extracted from red grapes in the processing of wine. Initially it was studied for its potential as anticancer drug, and later was found to reduce cardiovascular disease. More recently resveratrol was shown to alleviate depressive-like symptoms induced by stress or other means in mice and rats. The major purpose of this study was to investigate whether resveratrol would manifest an antidepressant effect in Wistar-Kyoto (WKY) rats, a putative and non-induced animal model of depression, and whether this effect might be associated with an increase in hippocampal and frontal cortical brain-derived neurotrophic factor (BDNF), a protein implicated in chronic effects of many antidepressants. Adult male WKY rats were injected with two doses of resveratrol (10 and 40 mg/kg, i.p.) and their behavior in the open field locomotor activity (LMA), forced swim test (FST: a measure of helplessness), and sucrose preference test (SPT: a measure of anhedonia) was evaluated after a single acute injection or following 7 days of daily treatment. Both acute and chronic administration of resveratrol resulted in a dose-dependent decrease in FST. However, only chronic resveratrol resulted in dose-dependent increase in sucrose consumption. LMA was not affected by any treatment. Parallel to the observed behavioral effects the level of hippocampal, but not frontal cortical, BDNF was also dose-dependently elevated after chronic resveratrol administration. These findings indicate an antidepressant-like effect of resveratrol in an animal model of depression possibly via activation of hippocampal BDNF, and suggest therapeutic potential of resveratrol in at least a subpopulation of depressed patients.

Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biological actions including antidepressant-like effects which have been observed in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10 d) with 50, 100, and 200mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1 hour after acute and 18–20 hours after last chronic injection. Results showed a dose-dependent reduction of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant.

Abstract:This review is an attempt to summarize our current understanding of curcumin's potential as a neuroprotectant and an antidepressant. This dual property confers a unique advantage to this herbal medication, believed to be devoid of any major side effects, to combat commonly observed co-morbid conditions of a neurodegenerative and a neuropsychiatric disorder. Moreover, in line with the theme of this series, the role of inflammation and stress in these diseases and possible anti-inflammatory effects of curcumin, as well as its interaction with signal transduction proteins as a common denominator in its varied mechanisms of action, are also discussed. Thus, following a brief introduction of curcumin's pharmacology, we present research suggesting how its anti-inflammatory properties have therapeutic potential in treating a devastating neurological disorder (Parkinson's disease = PD) and a debilitating neuropsychiatric disorder (major depressive disorder = MDD). It is concluded that curcumin, or better yet, an analog with better and longer bioavailability could be of important therapeutic potential in PD and/or major depression. CurcuminCurcumin, a diarylheptanoid, is the principal curcuminoid of the popular South Asian spice turmeric (Curcuma longa), which is a member of the ginger family (Zingiberaceae). Curcumin and turmeric's other two curcuminoids, desmethoxycurcumin and bisdesmethoxycurcumin are natural phenols responsible for the yellow color of turmeric. Indeed, because of its bright-yellow color, curcumin is used as a food coloring as well as food additive. Curcumin can exist in several tautomeric forms, however, the enol form is more stable in the solid phase and in solution [1].Curcumin's antioxidant [2][3][4], hepato-and nephroprotectant [5][6][7], antimicrobial [8,9], anti-inflammatory [10-13] and potential anti-depressant properties [14][15][16][17][18][19] are well documented. Epidemiological studies have demonstrated that societies that widely use curcumin show reduced incidence of inflammation-influenced and cognitive function diseases such as Alzheimer's disease [20][21][22][23]. It has also been suggested that curcumin may reduce the incidence of Parkinson's disease (PD), as some studies have shown an absence of age-related changes in nigral dopaminergic neurons in Indian populations that consume large amounts of curcumin [24][25][26]. Moreover, as discussed below, numerous in vitro and in vivo studies provide substantial evidence for a protective effect of curcumin against insults that may precipitate PD-like symptoms. Depression General ConsiderationsMajor depression is a disorder with many definitions and manifestations and with a 12-month prevalence rate of 6.3% to 10.3% in Western societies [27]. Symptoms may vary, but often include anhedonia, disrupted sleep patterns, lack of motivation, or emotional distress (e.g., anxiety). Although a number of clinically effective treatments are available, a large segment of patients are non-responsive (i.e., exhibit treatment-resistance to first-...