Delayed Treatment with Aminoguanidine Decreases Focal Cerebral Ischemic Damage and Enhances Neurologic Recovery in Rats

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Abstract
Delayed treatment with aminoguanidine (AG), a relatively selective inhibitor of inducible nitric oxide synthase, ameliorates brain damage produced by occlusion of the rat's middle cerebral artery (MCA). We investigated whether the protection exerted by AG is dose-dependent and whether it is associated with improved neurologic outcome. We also studied the effect of the timing of administration of AG relative to the induction of cerebral ischemia. Halothane-anesthetized spontaneously hypertensive rats underwent permanent MCA occlusion distal to the lenticulostriate branches. Neurologic deficits were assessed daily by the postural reflex test and beam balance test. Infarct volume was determined in thionin- stained sections 96 hours after ischemia and values corrected for swelling. Treatment with AG (intraperitoneally, twice daily), starting 24 hours after MCA occlusion, decreased neocortical infarct volume in comparison to vehicle-treated rats. After correction for swelling, the decrease was 8 ± 12% at 50 mg/kg (n = 8; P > .05; analysis of variance), 25 ± 13% at 100 mg/kg (n = 7; P < .05), 30 ± 16% at 200 mg/kg (n = 7; P < .05) and 32 ± 9% at 400 mg/kg (n = 5; P < .05). Twenty-four hours after induction of ischemia neurologic deficits scores did not differ between treated and untreated rats ( P > .05). However, from 48 to 96 hours after ischemia, neurologic deficits improved significantly in rats treated with AG (100 to 400 mg/kg) compared to rats in which vehicle was administered ( P < .05). The decrease in neocortical infarct volume was greatest when AG (100 mg/kg; twice daily) was administered 12 (26 ± 17%; n = 9) or 24 hours (25 ± 13; n = 7) after MCA occlusion. The findings show that AG decreases ischemic brain damage dose-dependently and improves neurologic recovery. Delayed treatment with AG may be a therapeutic strategy to selectively target the evolution of ischemic damage that occurs in the post-ischemic period.