EFFICACY OF GLUTAMATE-RECEPTOR ANTAGONISTS IN THE MANAGEMENT OF FUNCTIONAL-DISORDERS IN CYTOTOXIC BRAIN EDEMA INDUCED BY HEXACHLOROPHENE

The hexachlorophene-induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substanc es (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain da mage, we have studied the protective effects of several competitive an d non-competitive antagonists using adult male Wistar rats in a simple ''ladder-test'' for assessing coordinative motor behaviour. Hexachlor ophene-induced brain damage was verified by histological examination o f the cerebellum with vacuolation of white matter, astrocyte hypertrop hy and astrocyte proliferation taken as signs of neurotoxic injury. Th e non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine m aleate (MK-801) decreased the motor disturbance on the first and secon d day of the ''ladder-test'' when applied in the doses 0.1 mg/kg and 0 .2 mg/kg intraperitoneally for 3 weeks during the hexachlorophene trea tment. Acute MK-801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor resp onse only on the first day. When testing the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) in the dose 1.0 m g/kg intraperitoneally the motor disturbance was lowered significantly earlier than in spontaneous remission: Similar effects were observed with 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) in the dose of 0.8 m g/kg intraperitoneally, an antagonist interacting both with the strych nine-insensitive binding site for glycine within the NMDA receptor com plex and with the alpha-amino-3-hydroxy-5-methylisoxazole-4-proponic a cid (AMPA) receptor complex. Concurrent MK-801 administration decrease d the vacuolation of white matter. The results suggest that NMDA recep tors and non-NMDA receptors are involved in development of functional disorders induced by hexachlorophene.