Dietary Phytoestrogen ameliorates Ovarian Toxicant–induced Neurotoxicity: Mechanistic and metabolic insights

Most women undergoing accelerated ovarian failure experience cognitive-affective dysfunction, bioenergetic failure, amyloidogenic susceptibility, and persistent neuroinflammation, emerging chiefly from impaired estrogenic regulation. Despite the fact that ERT improves women's lives, it is not widely utilised due to the risk of thrombosis, cardiac issues, and endometrial cancer. The phytoestrogen diet (PED), renowned for its ERβ-centered neurorestorative potential, has shown considerable promise; however, the detailed mode of action remains largely underexplored. This study aims to elucidate the translational molecular mechanisms by which dietary phytoestrogen elicits neuroprotective benefits against ovatoxin-induced expedited cognitive ageing and neurodegenerative pathologies. We explored the therapeutic effects of PED using neurobehavioural paradigms, mitochondrial functional assessments, and estimates of neuronal atrophy and neuroinflammatory signalling via cell-specific dual immunofluorescence analyses. Additionally, we evaluated PED's efficacy in restoring the brain metabolite profile, identifying neurodegenerative signatures, and mitigating chronic neuroimmune transition. Results revealed that accelerated ovarian insufficiency exacerbated memory alterations and emotional instability, coinciding with decreased ER-β and BDNF expression, enhanced beta-amyloid deposition, and microgliosis-driven neuroimmune dysregulation. High-VIP metabolites reflected disruptions in steroid, sphingolipid, and fatty acid pathways, indicating that ovarian failure drives estrogen-dependent metabolic reprogramming. Our study demonstrated that PED rich in estrogen-mimicking isoflavones ameliorated mood and memory deficits by modulating beta-amyloid, reinstating mitochondrial integrity, rescuing the brain metabolome, and restoring neurotrophic signalling through ER-β activation in the mPFC. Therefore, PED is a promising candidate for treating neurocognitive decrements by potentiating ER-β activity, preserving mitochondrial integrity, and modulating the inflammopharmacological axis.