THE EFFECTS OF GAMMA(2)-MELANOCYTE-STIMULATING HORMONE AND NIMODIPINEON CORTICAL BLOOD-FLOW AND INFARCTION VOLUME IN 2 RAT MODELS OF MIDDLE CEREBRAL-ARTERY OCCLUSION

We observed that the pro-opiomelanocortin-derived neuropeptide, gamma( 2)-melanocyte-stimulating hormone (gamma(2)-MSH), has various peripher al and central hemodynamic effects in the rat, including a marked enha ncing effect on cerebral blood flow. This hemodynamic profile might be of interest in the pharmacotherapeutic approach to acute cerebral isc hemia. Being an adrenocorticotropin (ACTH) analogue, gamma(2)-MSH migh t also possess direct neuronal protective properties. Therefore, in tw o rat models of focal cerebral ischemia we studied the effects of gamm a(2)-MSH, with nimodipine, a Ca2+ channel antagonist, as a reference c ompound, on parasagittal laser-Doppler-as sessed cortical blood flow a nd infarction volume. In isoflurane-anesthetized Wistar and F344 rats i.v. bolus infusions (four in total) of gamma(2)-MSH or nimodipine or their vehicle controls were given 1 h before, 1 min after, and 1 h and 2 h after occlusion of the middle cerebral artery. We used both an in travasal and an extravasal middle cerebral artery occlusion technique because pilot experiments had shown differences in the severity of isc hemia with the two techniques. gamma(2)-MSH (100 nmol/kg in 1 min) inc reased cortical blood flow significantly but transiently, both pre- an d post-ischemically, whereas nimodipine (20 mu g/kg in 1 min) increase d cortical blood flow only pn-ischemically in both models of middle ce rebral artery occlusion. gamma(2)-MSH had no effect on cortical and st riatal infarction volume, while nimodipine caused a significant reduct ion of cortical infarction volume in the extravasal middle cerebral ar tery occlusion model. To conclude, despite its hemodynamic and possibl e neuroprotective properties, gamma(2)-MSH did not prevent ischemic ne uronal damage after middle cerebral artery occlusion in rats. This mig ht be partly due to the short half-life of the peptide, leading to a t ransient increase in cortical blood flow and short neuronal exposure t ime, suggesting that prolonged infusion of the neuropeptide might be r equired. The results with nimodipine support the notion that it attenu ates cortical ischemic damage, independently of effects on cerebral he modynamics.