Zinc as a Neuroprotective and Antioxidant Strategy in an Alzheimer-like Rat Model Induced by Ovariectomy and D-Galactose: A Clinicopathological and Therapeutic Review
Abstract
Alzheimer's disease is the most prevalent form of dementia globally, with postmenopausal women bearing a disproportionately higher risk attributable to the loss of estrogen's neuroprotective effects. The rat model combining bilateral ovariectomy and chronic D-galactose induction has been validated as a preclinical representation of sporadic postmenopausal AD, producing a clinicopathological profile encompassing elevated oxidative stress markers (increased MDA and decreased SOD activity), hippocampal amyloid-β42 accumulation, acetylcholinesterase hyperactivity, decreased expression of BDNF and Nrf2, elevated GSK-3β expression, and hippocampal histopathological degeneration. This review integrates these clinicopathological profiles across five interconnected domains: oxidative, amyloid, cholinergic, molecular, and histopathological and evaluates preclinical evidence for zinc as a multi-target therapeutic agent. Principal mechanisms identified include Nrf2-ARE pathway activation, M1/M2 microglial polarization modulation, support of BDNF expression, and indirect protection of cholinergic neuronal integrity. An observation across preclinical studies is that the relationship between zinc dosage and neuroprotection conforms to a U-shaped or inverted-U-shaped dose-response curve, making systematic dose-response evaluation essential for identifying optimal therapeutic doses. Key research gaps identified include the absence of systematic dose-response studies using zinc in the OVX+D-galactose model, limited exploration of therapeutic zinc administration following AD-like pathology establishment, and the uncharacterized role of the Nrf2 pathway under conditions of combined estrogen deficiency and D-galactose-induced oxidative stress. Addressing these gaps is essential for establishing zinc as a safe, accessible, and clinically relevant neuroprotective strategy for postmenopausal women at elevated Alzheimer's disease risk.