The effects of gamma 2-melanocyte-stimulating hormone and nimodipine on cortical blood flow and infarction volume in two 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 peripheral and central hemodynamic effects in the rat, including a marked enhancing effect on cerebral blood flow. This hemodynamic profile might be of interest in the pharmacotherapeutic approach to acute cerebral ischemia. Being an adrenocorticotropin (ACTH) analogue, gamma 2-MSH might also possess direct neuronal protective properties. Therefore, in two rat models of focal cerebral ischemia we studied the effects of gamma 2-MSH, with nimodipine, a Ca2+ channel antagonist, as a reference compound, on parasagittal laser-Doppler-assessed cortical blood flow and 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 intravasal and an extravasal middle cerebral artery occlusion technique because pilot experiments had shown differences in the severity of ischemia with the two techniques. gamma 2-MSH (100 nmol/kg in 1 min) increased cortical blood flow significantly but transiently, both pre- and post-ischemically, whereas nimodipine (20 micrograms/kg in 1 min) increased cortical blood flow only pre-ischemically in both models of middle cerebral artery occlusion. gamma 2-MSH had no effect on cortical and striatal infarction volume, while nimodipine caused a significant reduction of cortical infarction volume in the extravasal middle cerebral artery occlusion model. To conclude, despite its hemodynamic and possible neuroprotective properties, gamma 2-MSH did not prevent ischemic neuronal damage after middle cerebral artery occlusion in rats. This might be partly due to the short half-life of the peptide, leading to a transient increase in cortical blood flow and short neuronal exposure time, suggesting that prolonged infusion of the neuropeptide might be required. The results with nimodipine support the notion that it attenuates cortical ischemic damage, independently of effects on cerebral hemodynamics.
Herz
R C
RC
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Netherlands.
De Wildt
D J
DJ
Versteeg
D H
DH
D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D002540:Cerebral Cortex / Q000098:blood supply*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D009553:Nimodipine; D009074:Melanocyte-Stimulating Hormones