Genistein mitigates estrogen deficiency and chronic stress-induced neuronal dysfunction via targeting ER-β, oxidative stress, inflammation, and apoptosis.

Both postmenopausal estrogen decline and chronic unpredictable mild stress (CUMS) contribute to the onset and progression of brain dysfunctions in women. Genistein, a phytoestrogen predominantly found in soy and soy products, may reverse brain dysfunctions. Therefore, the current study focused on determining the effect of GEN in the modulation of brain dysfunction by using the Ovariectomized (OVX)-CUMS rat model. To induce postmenopausal brain dysfunction, female SD rats were bilaterally OVX and then exposed to CUMS for a total of 28 days. Various basic physiological and neurobehavioral parameters were performed. Oxidative stress was measured in the brain. Brain inflammation (TNF-α, IL-6, & NF-kB/p65), apoptotic (Bax) and anti-apoptotic (Bcl-2) markers were analyzed using RT-PCR and/or ELISA. Decreased estrogen levels and CUMS both combinedly cause a reduction in serum estradiol levels, downregulation of ER-α and ER-β genes, and enhancement of oxidative stress, neuroinflammation, and apoptosis. Collectively, all these factors were responsible for the development of neuronal dysfunctions. GEN at doses of 10 & 20-mg/kg significantly and dose dependently restores serum estradiol levels and ER-β gene expression. With this, genistein also reduces oxidative stress, apoptosis, and neuroinflammation in the brain of OVX-CUMS rats. Thus, GEN (10 & 20-mg/kg) dose-dependently restores the estrogen deficiency and chronic stress-induced brain dysfunction.