The effect of the adrenocorticotropin-(4-9) analogue, ORG 2766, and of dizolcipine (MK-801) on infarct volume in rat brain.
The purpose of this study was to evaluate whether the synthetic adrenocorticotropin-(4-9) (ACTH-(4-9)) analogue ORG 2766, HMet(O2)-Glu-His-Phe-D-Lys-Phe-OH, which has been shown to have beneficial effects on both the recovery from experimentally induced lesions of the central nervous system and peripheral nerve degeneration, has a protective effect on focal ischemic neuronal damage. The NMDA receptor antagonist dizolcipine (MK-801), a very potent neuroprotective drug, was used as positive reference compound. Isoflurane-anesthetized rats had the middle cerebral artery occluded using either an intravasal or an extravasal technique, because pilot experiments had shown differences in the severity of ischemia for the two middle cerebral artery occlusion techniques. MK-801, 500 microg kg(-1) min(-1), or saline was administered i.v. 30 min after occlusion of the middle cerebral artery. In the ACTH-(4-9) analogue/saline group, 10 and 150 microg/kg of the analogue, or saline was injected s.c. both directly after and 24 h after occlusion. The ACTH-(4-9) analogue treatment had no effect on the infarction volume in either model of middle cerebral artery occlusion, whereas MK-801 caused a significant reduction in the volume of cortical infarction in both models. We conclude that, although ORG 2766 is known to enhance the recovery from experimentally induced lesions of the central nervous system through a neurotrophic action and has proven to have significant beneficial effects on peripheral nerve regeneration, it did not prevent ischemic neuronal damage after intravasal or extravasal middle cerebral artery occlusion in rats. The results with MK-801, which caused significant reductions in the volume of cortical infarction in both models of middle cerebral artery occlusion, with clearly the largest reduction in the intravasal middle cerebral artery occlusion model, again indicate that there are differences in the severity of the cerebral ischemia which the two models produce in the rat brain.
Herz
R C
RC
Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Netherlands.
Kasbergen
C M
CM
Versteeg
D H
DH
De Wildt
D J
DJ
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D017078:Laser-Doppler Flowmetry; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C013765:Org 2766; D016291:Dizocilpine Maleate; D000324:Adrenocorticotropic Hormone