Differential effects of hypothermia and memantine in neonatal hypoxia-ischemia

Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxia-ischemia (HI), but its efficacy is limited. Understanding the molecular pathways involved in cell death and survival, while considering sex-related differences, is essential to optimize therapeutic strategies. This study evaluated the neuroprotective effects of memantine, a non-competitive NMDA receptor antagonist, alone or in combination with TH, in male and female neonatal rats subjected to HI. Seven-day-old pups (P7) underwent right common carotid artery occlusion followed by 90 min of hypoxia (8% O₂). Memantine (20 mg/kg, i.p.) was administered immediately after hypoxia, followed by TH (32 °C for 5 h). Neurobehavioral tests were performed at P8, and animals were euthanized at P9 for assessment of brain injury and analysis of cleaved caspase-3, p-Akt, Bcl-2, and Bax levels by Western blot. The results showed that the treatments reversed the deficits in the righting reflex in females, but not in males. Memantine and TH - combined or alone - reduced infarct volume in males, while in females, memantine alone exerted a neuroprotective effect. Cleaved caspase-3 levels were reduced in both sexes in groups treated with memantine; in females, this reduction was also observed following TH alone or in combination with memantine. In males, both memantine and TH - either combined or alone - increased the Bcl-2/Bax ratio. In females, only the individual treatments (memantine or TH alone) promoted this anti-apoptotic effect. These findings highlight a sex-dependent differential effect of memantine and TH on neuroprotection.