Neuroprotective effect of the kappa-agonist enadoline (CI-977) in rat models of focal cerebral ischaemia.
The neuroprotective efficacy of the kappa-opioid agonist enadoline (CI-977) was examined in two acute rat models of focal cerebral ischaemia [non-recovery (4 h) and recovery (24 h)]. In the non-recovery model, Sprague-Dawley rats were anaesthetized throughout the study period. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA). The amount of early ischaemic damage was assessed 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 cortical damage. Importantly, enadoline had no significant effect on any of the physiological parameters monitored (blood pressure, blood gases, glucose, pH). In the recovery model the left MCA was permanently occluded under isoflurane anaesthesia. Animals were allowed to recover and were killed 24 h later. The amount of ischaemic brain damage and swelling was assessed histologically. In this model pretreatment with enadoline at either 0.1, 0.3, or 1.0 mg/kg s.c. was followed by continuous 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 infarction 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 controls) and swelling (reduced by 47.8%). Therefore the kappa-opioid agonist enadoline affords dose-dependent neuroprotection in both the non-recovery and recovery models of focal cerebral ischaemia in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Hayward
N J
NJ
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, UK.
McKnight
A T
AT
Woodruff
G N
GN
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001929:Brain Edema / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology*; D002544:Cerebral Infarction / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000378:metabolism*
D001572:Benzofurans; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C067110:enadoline