CEREBRO-PROTECTIVE EFFECTS OF ENA713, A NOVEL ACETYLCHOLINESTERASE INHIBITOR, IN CLOSED-HEAD INJURY IN THE RAT

Focal ischemic brain damage and diffuse brain swelling occur in severe cases of traumatic head injury. Ischemia decreases brain acetylcholin e (ACh) levels and head trauma upregulates acetylcholinesterase (AChE) in experimental animal models. The present study determined whether a brain-selective AChE inhibitor, ENA713, given once, up to 2 h after c losed head injury (CHI) could reduce the vasogenic edema and accelerat e recovery from neurological deficits induced by the injury in rats. E NA713 1-5 mg/kg produced a dose-related inhibition of AChE ranging fro m 40-85% in the cortex and hippocampus. Doses of 1, 2 and 5 mg/kg, sig nificantly reduced the motor and neurological deficits and speeded rec overy, as indicated by measurements made 7 and 14 days after injury. T he two larger doses were still effective when injected 1 or 2 h after CHI. The acceleration by ENA713 of recovery of motor function was inde pendent of its reduction in body temperature and was prevented by the simultaneous injection of mecamylamine (2.5 mg/kg), but not by scopola mine (0.2 or 1 mg/kg). Edema in the contused hemisphere (24 h after in jury) and disruption of the blood brain barrier (4 h after injury) wer e significantly reduced (about 50%) by doses of 2 and 5 mg/kg, but not by 1 mg/kg. The data support the hypothesis that ENA713 exerts a neur oprotective effect in brain injury by preventing the decrease in choli nergic activity in cerebral vessels and in neurones. (C) 1998 Elsevier Science B.V.