DELAYED TREATMENT WITH AMINOGUANIDINE DECREASES FOCAL CEREBRAL ISCHEMIC DAMAGE AND ENHANCES NEUROLOGIC RECOVERY IN RATS

Delayed treatment with aminoguanidine (AG), a relatively selective inh ibitor of inducible nitric oxide synthase, ameliorates brain damage pr oduced by occlusion of the rat's middle cerebral artery (MCA). We inve stigated whether the protection exerted by AG is dose-dependent and wh ether it is associated with improved neurologic outcome. We also studi ed the effect of the timing of administration of AG relative to the in duction of cerebral ischemia. Halothane-anesthetized spontaneously hyp ertensive rats underwent permanent MCA occlusion distal to the lenticu lostriate branches. Neurologic deficits were assessed daily by the pos tural reflex test and beam balance test. Infarct volume was determined in thionin- stained sections 96 hours after ischemia and values corre cted 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 swe lling, 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). T wenty-four hours after induction of ischemia neurologic deficits score s did not differ between treated and untreated rats (P >.05). However, from 48 to 96 hours after ischemia, neurologic deficits improved sign ificantly in rats treated with AG (100 to 400 mg/kg) compared to rats in which vehicle was administered (P <.05). The decrease in neocortica l infarct volume was greatest when AG (100 mg/ kg; twice daily) was ad ministered 12 (26 +/- 17%; n = 9) or 24 hours (25 +/- 13, n = 7) after MCA occlusion. The findings show that AG decreases ischemic brain dam age dose-dependently and improves neurologic recovery. Delayed treatme nt with ACT may be a therapeutic strategy to selectively target the ev olution of ischemic damage that occurs in the post-ischemic period.