Reversal of neurotoxin-induced ornithine decarboxylase activity in rat cerebral cortex by nimodipine. A potential neuroprotective mechanism.
An increase in the activity of the enzyme ornithine decarboxylase has been shown to be associated with ischemia and other lesions of the nervous system. We have previously characterized the induction of ornithine decarboxylase in cerebral cortex following excitotoxin lesion of the nucleus basalis and have shown it to be sensitive to treatment with MK-801 up to 4 hours after the lesion and to be associated with an early increase in ornithine decarboxylase mRNA. In this study, we have used this model to investigate the effect of dihydropyridines on this response to lesion. Injection of 1 micrograms kainate into the nucleus basalis causes a large increase in ornithine decarboxylase activity that is maximal at 8 hours (292 pmol/mg/hr) when there is a 200-fold increase in ornithine decarboxylase activity compared with unoperated control animals (1.4 pmol/mg/hr). Treatment of animals with nimodipine either 5 minutes before or 60 minutes after lesion did not affect the maximal ornithine decarboxylase response at 8 hours. However, repeated injections (four of nimodipine, 10 mg/kg) significantly (p less than 0.001) attenuated the response to lesion by 75%. Injections were given 5 minutes before lesion and at 1.0, 3.5, and 6.0 hours after lesion. The efficacy of this treatment regimen indicated that maintaining a blockade of dihydropyridine-sensitive channels over this period was necessary to attenuate this induction of ornithine decarboxylase. To investigate the critical period over which dihydropyridines might be effective, their action at the earlier time point of 4 hours was tested where a significant induction of ornithine decarboxylase occurs (60 pmol/mg/hr).(ABSTRACT TRUNCATED AT 250 WORDS)
Gardiner
I M
IM
Department of Biochemistry, Charing Cross and Westminster Medical School, London, UK.
de Belleroche
J
J
D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D009553:Nimodipine / Q000008:administration & dosage / Q000494:pharmacology*; D009847:Olivary Nucleus / Q000187:drug effects / Q000502:physiology; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D051381:Rats
D009553:Nimodipine; D009955:Ornithine Decarboxylase; D007608:Kainic Acid