THE CYCLOOXYGENASE AND LIPOXYGENASE INHIBITOR BW755C PROTECTS RATS AGAINST KAINIC ACID-INDUCED SEIZURES AND NEUROTOXICITY

In this study the effect of the anti-inflammatory drugs indomethacin, ibuprofen, ebselen (PZ 51, 2-phenyl-1,2-benzoisoselenazol-3(2H)-one), and BW755C -amino-1-(m-(trifluoromethyl-phenyl)-2-pyrazoline) on kaini c acid (KA)-induced behavioral and neurochemical changes in rats was i nvestigated. Rats injected with KA (10 mg/kg s.c.) developed seizure a ctivity with a 20% mortality within the first 4 h and neuronal degener ation in the limbic system after 3 days. Pretreatment with the cycloox ygenase inhibitor indomethacin (10 mg/kg i.p.) augmented KA-induced ep ileptic activity and increased the mortality in status epilepticus to 80%. Another cyclooxygenase inhibitor, ibuprofen (20 mg/kg i.p.), and the lipoxygenase inhibitor ebselen (20 mg/kg i.p.) showed d no effect on KA-in duce d symptoms and neuro chemical changes. Application of th e cycle oxygenase/lipoxyge nase inhibitor BW755C (40 mg/kg i.p.) reduc ed the severity of seizures and protected significantly from irreversi ble brain lesions induced by KA. The marked reduction of glutamate dec arboxylase (GAD; 53.3 +/- 12.2% of control) and choline acetyltransfer ase (ChAT; 60.9 +/- 9.1% of control) activities in amygdala/pyriform c ortex and GAD activity in hippocampus (69.4 +/- 5.6% of control) obser ved 3 days after KA injection was abolished by BW755C treatment. Histo pathological analyses of brain tissue showed that treatment with BW755 C prevented the KA-induced nerve cell degeneration, edema, hemorrhages , and tissue necrosis in amygdala/pyriform cortex. However, some cell loss in the hippocampus was present, predominantly in its CA3 sector, and to a mild extent also in insular cortex and entorhinal/pyriform co rtex. Our results indicate that BW755C may inhibit seizure-induced bra in damage either through the blockade of both prostaglandin and leukot riene synthesis or by its action as an oxygen radical scavenger.