Effects of the NMDA antagonist CP-98,113 on regional cerebral edema and cardiovascular, cognitive, and neurobehavioral function following experimental brain injury in the rat

Abstract

The present study examined the effects of CP-98,113, an N-methyl- d-aspartate (NMDA) receptor blocker, on cardiovascular variables, neurobehavioral motor function, spatial memory deficits, and cerebral edema formation following lateral (parasagittal) fluid-percussion (FP) brain injury in the rat. In Study 1, we compared the cardiovascular effects of i.p. administration of CP-98,113 at 15 min postinjury at doses of 1 mg/kg, 2 mg/kg, 5 mg/kg, or 20 mg/kg ( n=8/dose). Animals receiving 1 mg/kg to 5 mg/kg CP-98,113 showed slight but nonsignificant decreases in blood pressure, while those receiving the highest dose (20 mg/kg) showed significant hypotension. Based upon those observations, the 5 mg/kg dose was chosen as the optimal dose for subsequent behavioral studies. In Study 2, 15 min following lateral FP brain injury of moderate severity (2.5 atm), animals randomly received either CP-98,113 (5 mg/kg, i.p., n=23) followed by a 24-h subcutaneous infusion (1.5 mg kg −1 h −1) by means of a miniature osmotic pump, or identical volume of vehicle ( n=24), and were evaluated for neurologic motor function ( n=11/drug vs. 11/vehicle), memory function, and cerebral edema ( n=12/drug vs. 13/vehicle). CP-98,113 (5 mg/kg) significantly attenuated neurologic motor dysfunction at 24 h ( p<0.01) and 2 weeks ( p<0.05) postinjury, reduced posttraumatic impairment in spatial memory observed at 48 h postinjury ( p<0.001), and significantly reduced focal brain edema in the cortex adjacent to the site of maximal injury at 48 h postinjury (injury penumbra) ( p<0.001). These results suggest that blockade of the NMDA receptor may attenuate the deleterious sequelae of traumatic brain injury.