Combination drug therapy and mild hypothermia - A promising treatment strategy for reversible, focal cerebral ischemia

Background and Purpose-Hypothermia has been suggested to be the most potent therapeutic approach to reduce experimental ischemic brain injury identifi ed to date, and mild hypothermia is increasingly used for neuroprotection d uring neurovascular surgery. We have recently demonstrated that combined ad ministration of tirilazad mesylate and magnesium provides for an overall en hanced neuroprotective effect. The present study was designed to determine whether the efficacy of mild hypothermia (33 degrees C) can be increased by combination pharmacotherapy with tirilazad and magnesium (MgCl2). Methods-Forty Sprague-Dawley rats were subjected to transient, middle cereb ral artery occlusion and were randomly assigned to 1 of 4 treatment arms (n = 10 each): (1) normothermia + vehicle, (2) normothermia + tirilazad + MgC l2, (3) hypothermia + vehicle, or (4) hypothermia + tirilazad + MgCl2. Cort ical blood flow was monitored by a bilateral laser-Doppler flowmeter, and t he electroencephalogram was continuously recorded. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed after 7 days. Results-Tirilazad + MgCl2, hypothermia, and hypothermia + tirilazad + MSCl2 reduced total infarct volume by 56%, 63%, and 77%, respectively, relative to controls. In animals treated with both hypothermia and combination pharm acotherapy, cortical infarction was almost completely abolished (-99%), and infarct volume in the basal ganglia was significantly reduced by 55%. In a ddition, this treatment provided for the best electrophysiological recovery and functional outcome. Conclusions-The neuroprotective efficacy of hypothermia can be increased by pharmacological antagonism of excitatory amino acids and free radicals by using clinically available drugs. This treatment strategy could be of great benefit when applied during temporary artery occlusion in cerebrovascular surgery.