Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats

Abstract

Background and purpose: Critical factors influencing the neuroprotective efficacy of postischemic hypothermia include depth, duration, and time of onset of cooling. In clinical practice, there is an unavoidable lag between the hypoxic-ischemic (HI) insult and the opportunity to initiate cooling. We hypothesized that early administration of a neuroprotective agent in combination with later-onset cooling could represent an effective therapeutic intervention after neonatal HI. We evaluated whether treatment with topiramate, a clinically available anticonvulsant, increased the efficacy of delayed post-HI hypothermia in a neonatal rat stroke model.

Methods: Postnatal day 7 (P7) rats underwent right carotid artery ligation followed by 1.5 hours of exposure to 8% oxygen. Fifteen minutes post-HI, animals received injections of topiramate (30 mg/kg) or PBS. Cooling was initiated 3 hours later ("delayed hypothermia") in all animals (3 hours, in 27 degrees C incubator). Functional outcome (forepaw response to vibrissae stimulation) and pathology (morphometric lesion measurements) were evaluated at P15 and P35.

Results: Neither topiramate nor delayed hypothermia alone conferred protection in this protocol. Combined treatment with topiramate and delayed hypothermia improved both performance and pathological outcome in P15 and P35 rats compared with PBS-treated animals that underwent delayed hypothermia concurrently. At P15, functional measures were better in topiramate-treated animals (mean correct forepaw response 9.3/10 versus 4.8/10; P<0.001), and there was >50% reduction in tissue loss (P<0.001); trends were similar at P35.

Conclusions: Our data provide the impetus for further evaluation of therapeutic approaches that combine drug therapy with delayed-onset cooling after neonatal HI brain injury.