Non-N-methyl-D-aspartate (NMDA) receptor antagonist 1,2,3, 4-tetrahydro-6-nitro-2,3-dioxo-benzo(f)quinoxaline-7-sulphonamide (NBQX) decreases functional disorders in cytotoxic brain oedema.

N-methyl-D-aspartate (NMDA) and non-NMDA receptors were found to be involved in development of functional disorders caused by hexachlorophene. In order to specify the role of glutamate receptors we studied the protective effects of the selective antagonist of the kainate/(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor/channel 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulphonamide disodium (NBQX) and of the non-competitive NMDA receptor antagonist ifenprodil tartrate on coordinative motor behaviour of adult male Wistar rats as assessed in a simple 'ladder-test'. Neurotoxic injury of the cerebrum after hexachlorophene administration and putative amelioration after treatment with test substances was demonstrated histologically. Hexachlorophene-induced motor disturbance remitted spontaneously when stopping the noxis, but remittance occurred significantly earlier when NBQX [0.45 and 0.6 mg/kg intraperitoneal (i.p.)] was applied as well. Ifenprodil (0.15 to 1.2 mg/kg) did not improve the motor function. Vacuolation of white matter of the whole cerebrum was observed after 3 weeks of treatment with hexachlorophene. These morphological alterations caused by hexachlorophene treatment [central nervous system (CNS) vacuolation] spontaneously revert only after 5-6 weeks. The 5-day duration with test substances was too short for remission of vacuolation which thus may not apply to the situation after treatment with glutamate antagonists, despite improvement of motor function. The results suggest that kainate/AMPA receptor channels are at least partially involved in the mechanism of brain damage induced by hexachlorophene, however, the polyamine binding site of the NMDA receptor evidently is not involved.

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.