| Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 1988: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1987: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1986: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1985: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Research Abstract |
The specific binding sites for phenytoin (PHT) were found to exist in the membrane fractions of rat brain. The binding activity of the sites was found to be suppressed by cellular lipids, tri- and di-phosphoinositides. Inositide response was determined using a slice experiment of rat brain cortex on the basis of the Berridge's method. Among the compounds tested which may be associated with seizure, carbachol, norepinephrine (NE) and a high concentration of potassium were observed to markedly stimulate the response. On the other hand, no stimulation was shown with pentylenetetrazol. No effects of antiepileptic drugs were observed on the stimulated response which occurred with carbachol.
The cyclic GMP (cGMP) levels were raised by various excitatory substances, e.g. excitatory amino acids (glutamate, NMDA, ibotenate), carbachol, a high concentration of potassium, and somatostatin. No changes in the cGMP levels were observed by inhibitory, substances, e.g. NE and GABA. The cAMP levels demo
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nstrated no such a tendency in parallele with excitatory substances. All the elevated cGMP levels with the excitatory substances were suppressed by pentylenetetrazol. It is likely that the cGMP levels are associated with occurring seizures and the function of pentylenetetrazol remains to be elucidated.
Effects of antiepileptics and Ca-channel antagonists on inositol trisphosphate (IP_3; a putative second messenger yielded from triphosphoinositides) binding and IP_3-induced ca release were examined. Antiepileptics (PHT, valproate) and Ca-channel antagonists (verapamil, diltiazm, flunarizine, nicardipine, cinnarizine), examined, did not significantly inhibit the IP_3-receptor binding. On the other hand, PHT, phenobarbital, carbamazepine inhibited the Ca-releasing activity of IP_3 in the cerebellar membrane fractions by approx. 20% at therapeutic concentrations. As the findings here seem to indicate divergent features of the IP_3 receptor, further work using microsomal fractions of purified receptor preparations will be required. Less
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