Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.

Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.