Neuroprotective effects of topiramate and memantine in combination with hypothermia in hypoxic-ischemic brain injury in vitro and in vivo

Abstract

Hypoxic-ischemic encephalopathy (HIE) is a major cause of perinatal mortality and subsequent severe neurological sequelae. Mild hypothermia is a standard therapy for HIE, but is used only in selected Reference Centers and in neonates >1800 g. Since neuronal death following HIE occurs by a cascade of events triggered by activation of glutamate receptors, we used in vitro and in vivo models of HIE to examine whether the AMPA/kainate receptor antagonist topiramate and the NMDA receptor antagonist memantine could exert neuroprotective effects, alone or in combination with hypothermia. For the in vitro experiments, rat organotypic hippocampal slices were exposed to a 30 min duration of oxygen-glucose deprivation (OGD): treatment with topiramate (1 μM) and memantine (10–30 μM) or hypothermia (35 °C or 32 °C) significantly attenuated CA1 damage after 24 h. The combination of hypothermia with topiramate and memantine enhanced their protective effect. For the in vivo experiments, we used 7 day-old rat pups subjected to permanent left common carotid artery occlusion followed by 120 min of hypoxia. Administration of topiramate or memantine (i.p., 20 mg/kg) immediately and 2 h after hypoxia or exposure to hypothermia (32 °C for 4 h beginning 1 h after hypoxia) significantly reduced the extent of the resulting infarct. The combination of topiramate or memantine with hypothermia elicited a reduction of the infarct that was greater than that produced by drugs or hypothermia alone. Notably, memantine displayed a higher degree of neuroprotection as compared to topiramate both in vitro and in vivo and, when used alone at 20 mg/kg in vivo, produced a greater reduction in brain damage than observed using topiramate in combination with hypothermia. These results suggest that memantine may be more advantageous than topiramate as a therapeutic agent in neonates with HIE treated with hypothermia.