NONCOMPETITIVE NMDA ANTAGONISTS AND ANTIOXIDANT DRUGS REDUCE STRIATALATROPHY AND FACILITATE RECOVERY OF FUNCTION FOLLOWING LESIONS OF THE RAT CORTEX

Following brain injury there is an excessive release of glutamate, a r eduction in levels of cellular Mg++, and the generation of oxygen free radicals. These processes may contribute to the severity of the behav ioral impairments seen following brain injury by leading to secondary neuronal degeneration. The present experiment investigates the relativ e effects of three drugs (MK-801, an NMDA antagonist; magnesium chlori de, an NMDA antagonist; and N-tert-butyl-alpha-phenylnitrone (PBN), an anti-oxidant and free radical scavenger) which disrupt different aspe cts of the pathophysiological process, in reducing these impairments. Direct comparisons of these drugs may determine if one treatment is mo re effective than another, or if one is detrimental. In addition, the effects of combination treatments including PBN and MK-801 or MgCl2, w ere examined. These combination treatment were aimed at the possibilit y of potentiating the beneficial effects observed after administration of these agents alone. Rats received unilateral electrolytic lesions of the somatic sensorimotor cortex followed by a regimen of MK-801 (1 mg/kg), MgCl2 (1 mmol/kg), PBN (100 mg/kg), MK-801 + PEN (1 mg/kg, 100 mg/kg), MgCl2, + PBN (1 mmol/kg, 100 mg/kg), or saline (1 ml/kg) begi nning 15 min following injury. Rats were tested on several sensorimoto r tasks (i.e. forelimb placing and foot-fault) for 43 days following t he cortical lesions. Rats receiving any of the single or combination d rug treatments showed a significant facilitation of recovery on the se nsorimotor tasks compared to saline control rats. On one behavioral te st (i.e. foot-fault) there was a significant further enhancement of th e recovery by combination treatments compared to the single treatment groups. These data are consistent with the idea that excessive release of glutamate, reduction in Mg++ levels, and free radical generation c ontribute to the severity of the behavioral impairments following cort ical injury, and that arresting these processes results in a facilitat ion of behavioral recovery. Anatomical analysis showed that all drug t reatments decreased the amount of atrophy seen in the ipsilateral stri atum. (C) 1997 Elsevier Science Ireland Ltd.