Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia

OBJECTIVE: Cell death after cerebral ischemia is mediated by release of exc itatory amino acids, calcium influx into cells, and generation of free radi cals. We examined the hypothesis that concurrent administration of tirilaza d, a well-known antioxidant, and magnesium, an antagonist of calcium and ex citatory amino acids, would result in a synergistic neuroprotective effect. METHODS: Sprague-Dawley rats were subjected to transient middle cerebral ar tery occlusion and assigned to one of four treatment arms (n = 10 in each): 1) vehicle, 2) tirilazad, 3) MgCl2, or 4) tirilazad and MgCl2. Cortical bl ood flow was recorded using laser Doppler flowmetry. Functional deficits we re quantified by performing daily neurological examinations. Infarct volume was assessed after 7 days. RESULTS: There was no difference in cortical blood flow among groups. Anima ls that received tirilazad or MgCl2 monotherapy had significantly better ne urological function compared with control animals only on postoperative Day s 3 and 4, whereas animals treated with both drugs had significantly better neurological function than did control animals from postoperative Days 2 t hrough 7. Magnesium reduced total infarct volume by 25% (nonsignificant), t irilazad by 48% (P < 0.05), and combination therapy by 59% (P < 0.05) compa red with control data. CONCLUSION: Combined therapy with antagonists of excitatory amino acids and free radicals provides better neuroprotection from the effects of transien t focal ischemia than does therapy with either antagonist alone. In contras t to many experimental agents, tirilazad and magnesium offer the advantage of being licensed for clinical use. This drug combination could be of great benefit when administered before temporary artery occlusion in patients un dergoing cerebrovascular surgery.