THE EFFECT OF THE ADRENOCORTICOTROPIN-(4-9) ANALOG, ORG-2766, AND OF DIZOLCIPINE (MK-801) ON INFARCT VOLUME IN RAT-BRAIN

The purpose of this study was to evaluate whether the synthetic adreno corticotropin-(4-9) (ACTH-(4-9)) analogue ORG 2766, HMet(O-2)-Glu-His- Phe-D-Lys-Phe-OH, which has been shown to have beneficial effects on b oth the recovery from experimentally induced lesions of the central ne rvous system and peripheral nerve degeneration, has a protective effec t on focal ischemic neuronal damage. The NMDA receptor antagonist dizo lcipine (MK-801), a very potent neuroprotective drug, was used as posi tive reference compound. Isoflurane-anesthetized rats had the middle c erebral artery occluded using either an intravasal or an extravasal te chnique, because pilot experiments had shown differences in the severi ty of ischemia for the two middle cerebral artery occlusion techniques . MK-801, 500 mu g kg(-1) min(-1), or saline was administered i.v. 30 min after occlusion of the middle cerebral artery. In the ACTH-(4-9) a nalogue/saline group, 10 and 150 mu g/kg of the analogue, or saline wa s 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 ei ther model of middle cerebral artery occlusion, whereas MK-801 caused a significant reduction in the volume of cortical infarction in both m odels. We conclude that, although ORG 2766 is known to enhance the rec overy from experimentally induced lesions of the central nervous syste m through a neurotrophic action and has proven to have significant ben eficial effects on peripheral nerve regeneration, it did not prevent i schemic neuronal damage after intravasal or extravasal middle cerebral artery occlusion in rats. The results with MK-801, which caused signi ficant reductions in the volume of cortical infarction in both models of middle cerebral artery occlusion, with clearly the largest reductio n in the intravasal middle cerebral artery occlusion model, again indi cate that there are differences in the severity of the cerebral ischem ia which the two models produce in the rat brain. (C) 1998 Elsevier Sc ience B.V.