Role of Oxidative Stress in Behavioral, Cognitive and Biochemical Impairment in a Rat Model of Social Stress

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Psychological stress is known to contribute to anxiety and cognitive impairment in humans. Currently, the drugs of choice for treatment of anxiety disorders are traditional-antidepressants, with modest efficacy and major side effects. Therefore, alternative therapies with higher efficacy and fewer side effects are needed. Recent evidence from our lab has suggested a causal role of oxidative stress (OS) in psychological stress (social defeat)-induced behavioral and cognitive impairments in rats. Basically, psychological stress induces behavioral and cognitive deficits in rats while increasing oxidative stress systemically as well as in the brain. Increase in oxidative stress was associated with reduced systemic and cerebral antioxidant status. Imbalance in oxidant-antioxidant status seemed to have contributed to stress-induced deficits in the social defeat (SD) model. If the rise in oxidative stress causes behavioral and cognitive deficits then interventions mitigating oxidative stress by increasing antioxidant could be useful. In this study, we employed the rat model of social defeat (SD) which closely resembles societal stress in humans to determine whether increasing antioxidant level using grape powder (GP), with its rich antioxidant content, is able to protect and/or reverse SD-induced behavioral and cognitive deficits in rats. Grape powder is a mixture of a variety of antioxidants. Therefore, it is important to know which antioxidant constituent contributes to potentially protective effects of GP. This was determined in a neuronal cell culture model of HT22 cells, a hippocampal derived cell line. Finally, underlying mechanism(s) of action of GP also were determined. Sprague Dawley rats after undergoing 7 days of repeated social defeat developed significant behavioral and cognitive impairments. And, 3 weeks GP treatment (15 g/L in drinking water) protected and reversed SD-induced behavioral and cognitive deficits. Biochemical analysis revealed that GP treatment significantly decreased SD-induced increase in levels of plasma corticosterone (systemic marker of stress), and plasma 8-isoprostane (marker of OS). Furthermore, GP treatment significantly increased SD-induced decrease in cellular pool of key antioxidant enzymes such as glyoxalase-1, glutathione reducatse-1 and superoxide dismutases in specific regions of the brain including the hippocampus and amygdala. Next, utilizing an in-vitro model of oxidative stress, we examined contribution of Quercetin (Q), Resveratrol (R) and Kaempferol (K), key antioxidants present in grapes, in mediating protective effect. HT22 cells were treated with 1mM BSO (L-Buthionine-sulfoximine, pro-oxidant) for 14 hrs to induce oxidative stress. The cells were treated for 4 hrs with Q, R or K prior to BSO treatment. Q and R but not K were the most effective in protecting BSO-induced decreased total antioxidant capacity, suggesting major contribution of Q and R in protective action of grape powder. Further data suggested that GP protected oxidative stress-induced cell death by preventing oxidative stress-induced increased calcium influx, mitochondrial dysfunction and release of cytochrome c. Collectively, animal and cell culture data suggest that GP protected and reversed SD-induced behavioral and cognitive impairments in rats and, that quercetin and resveratrol appear as the most likely major contributors towards beneficial effects of GP. Finally, it seems that GP mitigates oxidative stress by increasing antioxidant pool and preventing cell damage and death.

Oxidative stress, Grape powder, Social defeat, Anxiety- and depression-like behavior, HT22 cells