Efficacy of glutamate receptor antagonists in the management of functional disorders in cytotoxic brain oedema induced by hexachlorophene.
The hexachlorophene-induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substances (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain damage, we have studied the protective effects of several competitive and non-competitive antagonists using adult male Wistar rats in a simple "ladder-test" for assessing coordinative motor behaviour. Hexachlorophene-induced brain damage was verified by histological examination of the cerebellum with vacuolation of white matter, astrocyte hypertrophy and astrocyte proliferation taken as signs of neurotoxic injury. The non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801) decreased the motor disturbance on the first and second 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 treatment. Acute MK-801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor response only on the first day. When testing the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) in the dose 1.0 mg/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 mg/kg intraperitoneally, an antagonist interacting both with the strychnine-insensitive binding site for glycine within the NMDA receptor complex and with the kainate(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor complex. Concurrent MK-801 administration decreased the vacuolation of white matter. The results suggest that NMDA receptors and non-NMDA receptors are involved in development of functional disorders induced by hexachlorophene.
Häntzschel
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Institute of Pharmacology and Toxicology, Faculty of Medicine, Technical University Dresden, Germany.
Andreas
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K
D015763:2-Amino-5-phosphonovalerate / Q000627:therapeutic use; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006582:Hexachlorophene; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D006582:Hexachlorophene