NEUROPROTECTIVE EFFECT OF THE KAPPA-AGONIST ENADOLINE (CL-977) IN RATMODELS OF FOCAL CEREBRAL-ISCHEMIA

The neuroprotective efficacy of the kappa-opioid agonist enadoline (CI -977) was examine in two acute rat models of focal cerebral ischaemia [non-recovery (4 h) and recovery (24 h)]. In the non-recovery model, S prague - Dawley rats were anaesthetized throughout the study period. F ocal ischaemia was produced by the permanent occlusion of the left mid dle cerebral artery (MCA). The amount of early ischaemic damage was as sessed in coronal sections at nine pre-determined stereotaxic planes. Enadoline at doses of 0.1, 0.3 and 1.0 mg/kg (n = 8), administered s.c . 30 min prior to ischaemia, produced dose-dependent amelioration of c ortical damage. Importantly, enadoline had no significant effect on an y of the physiological parameters monitored (blood pressure, blood gas es, glucose, pH). In the recovery model the left MCA was permanently o ccluded under isoflurane anaesthesia. Animals were allowed to recover and were killed 24 h later. The amount of ischaemic brain damage and s welling was assessed histologically. In this model pretreatment with e nadoline at either 0.1, 0.3, or 1.0 mg/kg s.c. was followed by continu ous s.c. infusion at 0.017, 0.05 or 0.17 mg/kg/h respectively (n = 8 - 17). Enadoline produced dose-dependent reductions in the volumes of i nfarction and brain swelling; the greatest reductions were seen at 1.0 mg/kg plus 0.17 mg/kg/h in both infarction (reduced by 37.4% from con trols) and swelling (reduced by 47.8%). Therefore the kappa-opioid ago nist enadoline affords dose-dependent neuroprotection in both the non- recovery and recovery models of focal cerebral ischaemia in the rat. I n the recovery model enadoline was effective in reducing infarction an d oedema; the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.