Dietary phytoestrogen ameliorates ovarian toxicant-induced neurotoxicity: mechanistic and metabolic insights.

Premature ovarian insufficiency (POI) poses serious neurological risks such as mood disturbances, cognitive decline, early brain structural changes, neural degeneration, and a heightened risk of dementia and AD in women. This study aims to investigate cognitive performance, mitochondrial malfunction, and persistent neuroinflammation in a mouse model of premature ovarian failure induced by ovatoxin vinylcyclohexene diepoxide (VCD), as well as the potential use of dietary phytoestrogen therapy to combat the accelerated brain ageing-like phenotype and chronic inflammation associated with ovarian insufficiency. The data from our neurobehavioural evaluations showed impaired object recognition memory, along with enhanced anxiety and depression in the VCD-intoxicated mice. This was accompanied by a water maze assessment, which indicates that long-term estrogen depletion negatively affected spatial learning and memory retrieval. This is demonstrated by the increased time required for VCD mice to locate the hidden platform and their inability to find the virtual platform during the memory retrieval assessment. In VCD-challenged mice, there were clear signs of compromised learning and memory across the behavioural tests, along with impaired mitochondrial complexes and increased β-amyloid protein expression. Furthermore, in conjunction with reduced estrogen levels, VCD mice showed enhanced neuronal inflammation, as evidenced by heightened expression of neuroinflammatory mediators, including HMGB1, TLR-4, NF-kappa B, CD68 and TREM2. Furthermore, our study has shown that a phytoestrogen diet can restore compromised mood and memory functions. The improvements in learning, memory, and cognitive abilities associated with this dietary intervention were evidenced by reduced neuroinflammation, restored mitochondrial respiratory complexes, enhanced neurotrophic factor levels, and decreased β-amyloid protein expression. Consequently, the current results provide preliminary support for the hypothesis that a diet rich in phytoestrogens could be a viable strategy to mitigate accelerated brain ageing and address mood and memory challenges associated with ovarian insufficiency.