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 (3-amino-1-(m-(trifluoromethyl-phenyl)-2-pyrazoline) on kainic acid (KA)-induced behavioral and neurochemical changes in rats was investigated. Rats injected with KA (10 mg/kg s.c.) developed seizure activity with a 20% mortality within the first 4 h and neuronal degeneration in the limbic system after 3 days. Pretreatment with the cyclooxygenase inhibitor indomethacin (10 mg/kg i.p.) augmented KA-induced epileptic 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 no effect on KA-induced symptoms and neurochemical changes. Application of the cyclooxygenase/lipoxygenase inhibitor BW755C (40 mg/kg i.p.) reduced the severity of seizures and protected significantly from irreversible brain lesions induced by KA. The marked reduction of glutamate decarboxylase (GAD; 53.3 +/- 12.2% of control) and choline acetyltransferase (ChAT; 60.9 +/- 9.1% of control) activities in amygdala/pyriform cortex and GAD activity in hippocampus (69.4 +/- 5.6% of control) observed 3 days after KA injection was abolished by BW755C treatment. Histopathological analyses of brain tissue showed that treatment with BW755C prevented the KA-induced nerve cell degeneration, edema, hemorrhages, and tissue necrosis in amygdala/pyriform cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
Baran
H
H
Institute of Biochemical Pharmacology, University of Vienna, Austria.
Vass
K
K
Lassmann
H
H
Hornykiewicz
O
O
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D054833:Isoindoles; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009928:Organ Specificity; D016566:Organoselenium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D016861:Cyclooxygenase Inhibitors; D054833:Isoindoles; D016859:Lipoxygenase Inhibitors; D016566:Organoselenium Compounds; C042986:ebselen; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D007608:Kainic Acid; D007052:Ibuprofen; D007213:Indomethacin