Potential of intranasal caffeine as a delivery route for treating glutamate-linked hippocampal neurodegeneration by activating endogenous antioxidant defenses.

BACKGROUND: Glutamate-induced excitotoxicity is one of the key pathological mechanisms in neurodegenerative disorders, contributing to memory impairment, oxidative stress, and progressive neuronal degeneration. Caffeine has demonstrated neuroprotective properties by reducing oxidative damage and modulating hippocampal neuronal apoptosis. Intranasal (IN) administration provides a non-invasive and efficient route for direct brain delivery, minimizing systemic exposure and side effects. This study investigated the neuroprotective effects of IN caffeine in a monosodium glutamate (MSG)-induced excitotoxicity model. METHODS: Male Wistar rats received MSG (4 g/kg, i.p., 5 days/week for three weeks) to induce excitotoxicity. Animals were randomized into five groups (n = 7 per group): Saline (control), MSG+Saline (model), and MSG+Caffeine at 1, 3, and 6 mg/kg. Over 5 days/week administration for three weeks, behavioral memory function was assessed using a Y-Maze test. Molecular assessments included RT-qPCR for BDNF, Bcl-2, BAX, Nrf2, and HO-1 expression; Biochemical assays for SOD, CAT, and GPx; and MDA levels in the hippocampus. Histological analysis of hippocampal subregions (DG, CA1, CA3) and nasal mucosa was conducted to assess neuronal survival and safety, respectively. RESULTS: MSG-treated rats exhibited significant memory impairment and neuronal loss, which were attenuated by caffeine treatment. Caffeine significantly increased BDNF and Bcl-2 gene expression and downregulated pro-apoptotic BAX compared to the MSG+Saline group (p < 0.01). Antioxidant defenses were restored, shown by significant upregulation of gene expression of Nrf2 and HO-1 (p < 0.05) and increased activity of SOD, CAT, and GPx alongside a significant reduction in MDA levels (p < 0.01). Notably, the results showed no clear dose-dependent response across these three dosages, and all were within the therapeutic window for neuronal function. Histopathological examination of the nasal mucosa revealed only mild inflammatory changes in the 1 and 3 mg/kg groups, while the 6 mg/kg group exhibited no detectable mucosal abnormalities. CONCLUSIONS: These findings support the therapeutic potential of IN caffeine as a promising non-invasive strategy against glutamate-induced neurotoxicity. Further studies are needed to optimize the dose, treatment duration, and IN delivery to maximize efficacy and enhance nasal safety.