Pre- and post-stroke memantine administration attenuates neurological deficits, infarct size, and astrogliosis, with a concomitant increase in MAP2 protein in a rat stroke model.

Over the past 30 years, the global incidence of stroke and related disability-adjusted life years has risen significantly, underscoring the urgent need for effective therapeutic strategies. Memantine (Mem), a non-competitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, has been investigated as a potential treatment in stroke models. By blocking NMDA receptor activity, Mem can prevent excessive calcium influx and excitotoxic neuronal death, thereby promoting neuroprotection with good tolerability. Because early intervention is crucial, we evaluated a sequential memantine regimen in 32 male Sprague-Dawley rats (300-350 g). A low dose of Mem (0.2 mg/kg) was administered before permanent middle cerebral artery occlusion (pMCAO), followed by a higher dose (10 mg/kg) two hours after occlusion. Neurological function was evaluated 24 h later using the modified Neurological Severity Score (mNSS). Brain tissue was collected for immunohistochemical analysis of glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP2) near the infarct area. Enzyme-linked immunosorbent assays (ELISA) measured brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95). Memantine treatment preserved neurological function, reduced infarct size, and decreased GFAP levels, indicating diminished astrocyte reactivity. Additionally, MAP2 presence increased compared to the untreated pMCAO group, suggesting neuronal preservation. No significant changes were observed in BDNF or PSD95 levels. Memantine administered before and after stroke minimized tissue loss and prevented early astrogliosis, while preserving neuronal structural integrity as indicated by MAP2. In contrast, no immediate changes were detected in BDNF or PSD95, implying that memantine-induced neuroprotection occurs before the appearance of plasticity-related molecular adaptations in the early post-stroke period.