Protective effect of eptazocine, a novel analgesic, against cerebral ischemia in mice and rats

Abstract

The cerebral protective effect of eptazocine, an opioid μ-antagonist-κ-agonist, was investigated using mice and rats subjected to ischemia. 1) Decapitation or concussive head injury (20 g, 30 cm) -induced ischemia in mice : Eptazocine (3, 10 mg/kg) prolonged the gasping duration or the survival time in a dose-dependent manner. 2) Ischemic brain edema induced by bilateral carotid arterial occlusion (BLCO) in rats: Administration of eptazocine just after BLCO treatment significantly prevented the incidence of ischemic seizures, lethality and an increase in cerebral water content. 3) Acute ischemic changes in cerebral energy metabolism in mice : 2-min BLCO treatment decreased the cerebral contents of phosphocreatine and ATP, and it increased the contents of AMP and lactate, resulting in a 34% decrease in energy charge potential and an increase in lactate/pyruvate ratio. Such changes were improved by eptazocine (3, 10 mg/kg)and ethylketocyclazocine (3 mg/kg), a κ-agonist. 4) Respiratory function in mouse brain mitochondria preparations : Eptazocine increased the State 3 respiration and respiratory control index (RCI : State 3/State 4), and it prevented a decrease in RCI induced by 3-min ischemia. These results suggest that eptazocine may improve cerebral ischemic disorders through an activation and/or protection of mitochondrial energy-producing systems.