Effects of Zinc Deficiency and Supplementation on Hippocampal ZnT3, NOGO-A, IL-6, and SESN2 Expression and Oxidative Stress Markers in a Cuprizone-Induced Toxic Demyelination Model

This study investigated the effects of zinc deficiency and supplementation on oxidative stress markers and the expression of ZnT3, NOGO-A, IL-6, and SESN2 in hippocampal tissue within a cuprizone (CPZ)-induced toxic demyelination model. Methods: Forty-six adult male Wistar rats were divided into five groups: Control (n = 6), Sham (n = 10), CPZ (n = 10), CPZ + zinc-deficient diet (n = 10), and CPZ + zinc supplementation (5 mg/kg/day, i.p., n = 10). Toxic demyelination was induced by continuous cuprizone administration for eight weeks. At the end of the experimental period, hippocampal malondialdehyde (MDA) and glutathione (GSH) levels were measured; additionally, hippocampal ZnT3, NOGO-A, IL-6, and SESN2 mRNA expression levels were analyzed using quantitative real-time PCR. Cuprizone administration led to significant hippocampal oxidative stress, characterized by increased MDA levels and decreased GSH concentrations (p < 0.05); these oxidative changes were further exacerbated in CPZ-treated animals fed a zinc-deficient diet (p < 0.05). Furthermore, CPZ-induced demyelination suppressed ZnT3 expression in hippocampal tissue while significantly increasing NOGO-A, IL-6, and SESN2 mRNA expression (p < 0.05). These molecular alterations were more pronounced in the zinc-deficient CPZ group (p < 0.05). Intraperitoneal zinc supplementation effectively mitigated these changes by suppressing oxidative stress, attenuating the upregulation of NOGO-A, IL-6, and SESN2 transcripts, and restoring ZnT3 expression to levels comparable to controls (p < 0.05). While dietary zinc deficiency exacerbated hippocampal oxidative stress, neuroinflammatory transcripts, and molecular markers associated with neurodegeneration in the cuprizone model, zinc supplementation restored oxidative balance; increased ZnT3 expression; and suppressed the upregulation of NOGO-A, IL-6, and SESN2. These findings suggest that zinc homeostasis significantly modulates cuprizone-induced hippocampal damage and that zinc supplementation may exert protective transcriptional and antioxidant effects during toxic demyelination.