Rivastigmine, a Brain-Selective Acetylcholinesterase Inhibitor, Ameliorates Cognitive and Motor Deficits Induced by Closed-Head Injury in the Mouse

Abstract

The effects of Rivastigmine, a novel centrally-acting anticholinesterase agent, were evaluated on cerebral edema, neurological and motor deficits, and impairment of spatial memory induced in mice by closed-head injury (CHI). Severe injury was induced in the left hemisphere of mice under ether anesthesia. Rivastigmine (1 or 2 mg/kg) or saline (10 ml/kg) was injected SC 5 min later. Rivastigmine (2 mg/kg) reduced cerebral edema by at least 50% (p < 0.01), 24 h after CHI and accelerated the recovery of motor function 7 and 14 days after CHI. Control mice (n = 24), previously trained to find the goal platform in a Morris water maze failed to recall or relearn its position for at least 11 days post-injury. Those given a single injection of Rivastigmine (2 mg/kg) regained their pre-test latencies by the third day after CHI. The neuroprotective effects of Rivastigmine on brain edema, neurological and motor function, and performace in the Morris water maze were completely antagonized by simultaneous SC injection of either scopolamine (0.5 mg/kg) or mecamylamine (2.5 mg/kg). The antagonists alone had no significant effect on any of these parameters. These data show that the reduction by Rivastigmine of the immediate and long-term sequelae of brain injury are mediated by increased cholinergic activity at both muscarinic and nicotinic receptors.