Estrogen Receptor β Mediated Neuroprotective Efficacy of Cicer microphyllum Seed Extract in Global Hypoxia

Hypoxia induced oxidative stress and neurodegeneration in the hippocampus has been implicated for memory impairment in conditions like stroke, ischemia and hypobaric hypoxia. The present study, aimed at investigating the potential of ethanolic extract of Cicer microphyllum seeds (CSE) for amelioration of global hypoxia induced neurodegeneration in CA1 region of hippocampus. CSE supplementation considerably reduced neurodegeneration and dendritic atrophy in CA1 neurons along with improvement of memory in hypoxic rats. This effect of CSE was partly attributed to its antioxidant activity resulting in reduction of lipid peroxidation, protein oxidation and DNA damage during exposure to chronic hypoxia. CSE also promoted dendritic arborization through activation of estrogen receptor beta (ERβ) and phosphorylation of extracellular signal regulated kinase (ERK1/2) which was independent of brain derived neurotrophic factor (BDNF) mediated signalling mechanisms. Extra nuclear activation of ERK1/2 by ERβ resulted in phosphorylation of cyclic AMP response element binding protein (CREB) leading to increased expression of PSD-95.These molecular alterations translated to behavioural changes in CSE administered hypoxic animals that performed better in Morris Water Maze Task as compared to vehicle treated hypoxic animals. Toxicological studies show NOEAL > 2000 mg/kg b.w. for oral administration of CSE indicating its safety for consumption. Our findings not only suggest the neuroprotective potential of CSE in hypoxia but also provide evidence for involvement of estrogen receptor and pCREB mediated nootropic effect of the extract.