Ca＋＋拮抗剤flunarizineの虚血脳保護作用に関する実験的検討

CEREBRAL PROTECTIVE EFFECT OF FLUNARIZINE IN A CANINE MODEL OF CEREBRAL ISCHEMIA

　抄録　脳虚血時の病態にCa^＋＋が関与することが指摘されて以来，種々のCa^＋＋拮抗剤の脳保護作用についての検討がなされている。今回はCa^＋＋拮抗剤の一つであるflunarizine （fnz）の脳保護作用について実験的に検討した。実験モデルとして"完全虚血脳灌流モデル犬"を用い，薬剤の虚血前投与後，脳血流をlaser-doppler血流計により測定しつつ正常時の10％の虚血状態を1時間維持し，その後血流再開を行ない，脳波の回復，脳腫脹の程度，Evans blue （EB）の漏出を観察することにより薬剤の効果を判定した。実験は無治療群5頭，fnz 1mg／kg投与群5頭，fnz 3mg／kg投与群5頭の3群に分けて行なった。結果は脳波の回復に関して，fnz投与群では用量依存性に良好な脳波の回復が得られ，無治療群に対して推計学的有意差が認められた。しかし脳腫脹およびEB漏出度に関してはfnz投与群では抑制効果は認められず，無治療群に対しても有意差は認められなかった。

Recently there is the hypothesis proposing that ischemic brain damage is associated with intra-cellular accumulation of calcium (Ca⁺⁺). Therefore a variety of experiments have been carried out to investigate whether a Ca⁺⁺-entry blocker was able to protect against brain damage caused by ische-mia. The purpose of the present experiment is to study the protective effects of a Ca⁺⁺an-tagonist, flunarizine, on cerebral ischemia.

In this experiment fifteen dogs were subjected to ischemia, using the "canine model of the com-pletely ischemic brain regulated with a perfusion method" in which the cerebral blood flow (CBF) can be fully regulated. Five animals served as untreated controls, ten received treatment with flunarizine (1 mg/kg in five dogs and 3 mg/kg in five dogs, respectively). This agent was admini-stered intravenously 20 minutes prior to the pro-duction of ischemia, when cerebral blood flow was reduced to one-tenth its normal value while monitoring CBF by means of a laser-Doppler flow meter. After one hour CBF was restored and the recovery of electrical activity of the brain and the degree of brain swelling were observed for three hours. At the end of the experiments, the degree of extravasation of Evans blue in the excised brain was examined.

With regard to the recovery of EEG, no recovery of EEG was seen subsequent to recirculation except one dog in the control group. Whereas in the groups treated with flunarizine, remarkable re-covery of EEG was found following recirculation in a dose dependent fasion. But concerning the degree of brain swelling and the degree of ex-travasation of Evans blue, no significant difference was found between untreated control group andflunarizine treated groups.

The present experiment thus suggests that the treatment of flunarizine is of benefit to functionalrecovery against cerebral ischemia, but does not suppress ischemic brain edema.