Monotherapy with dextromethorphan or tirilazad - but not a combination of both - improves outcome after transient focal cerebral ischemia in rats

Cell death after cerebral ischemia is mediated by a massive release of excitatory amino acids, generation of free radicals, and - a crucial step - calcium influx into cells. We examined the hypothesis that concurrent administration of drugs ameliorating brain damage via different mechanisms would result in a synergistic neuroprotective effect. The neuroprotective efficacy of two clinically available drugs - the N-methyl-D-aspartate and calcium-channel antagonist dextromethorphan (DM) and the antioxidant tirilazad - were studied in monotherapy and in combination in a rat model of transient focal ischemia. Male Sprague-Dawley rats were subjected to 90 min of middle-cerebral-artery occlusion by an intraluminal filament technique. The animals were randomly assigned to one of four treatments (n = 10 each): (1) vehicle-treated controls, (2) DM, (3) tirilazad, (4) DM+tirilazad. Drugs or vehicles were administered 15 min before ischemia and at reperfusion. Local cerebral blood flow (LCBF) was bilaterally recorded by continuous laser Doppler flowmetry. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed planimetrically after 7 days. DM prevented post-ischemic hypoperfusion. Tirilazad did not influence LCBF. Monotherapy with DM or tirilazad improved neurological function and reduced infarct volume by 45% and 48%, respectively. Combination therapy failed to influence neurological recovery and infarct volume. Although, from pharmacological point of view, a synergistic neuroprotective effect is expected, combination of dextromethorphan and tirilazad may lead to mutual inhibition or potentiate adverse effects.