Synergistic Effect of Allopurinol and Phenytoin in Ameliorating Ischemic Brain Infarction in the Rat

Allopurinol與phenytoin合併使用對減輕大白鼠缺血性腦梗塞之增強效應

王家儀(Jia-Yi Wang) ； 陳春珠(Chun-Chu Chen) ； 譚志高(Job Jyh-Gau Don) ； 江漢光(Hann-Kuang Jiang) ； 沈友直(Andrew Yau-Chik Shum)

《Journal of Medical Sciences》 13卷1期 (1992/08) Pp. 17-30

摘要

本實驗評估allopurinol及phenytoin對局部腦缺血所引起之腦梗塞之治療及預防效果。此二種藥物之作用機轉完全不同：allopurinol為xanthine oxidase抑制藥，以及可能為一種氧游離基清除劑；而phenytoin為抗痙攣劑，具有細胞膜穩定之作用。局部性腦缺血乃是利用大白鼠中大腦動脈阻塞之模式，其方法為由預先結紮右側中大腦動脈及同側之頸總動脈，於實驗開始時再夾住對側之頸總動脈六十分鐘，來造成局部腦缺血，被夾之左頸動脈於六十分鐘之後再放開，如此可以再灌流，再經24小時後將動物犧牲，取出腦組織以評估損傷之程度，其方法是由triphenyl-tetrazolium chloride對腦組織切片之活體性染色（Vital stain）之情形，並配合電腦影像處理程式，將因為缺血而造成之梗塞體積（不染色部位）計算出來，結果顯示我們之缺血－再灌流式所造成之腦半球梗塞體積為144.94 ± 21.34 mm^3。利用這種動物模式我們評估了二種藥物allopurinol及phenytoin在腦缺血之前後以個別給藥及合併投藥之方式，對腦梗塞體積大小之影響。缺血前6小時口服給予allopurinol（劑量100及200 mg/kg），可顯著減低梗塞體積，但是缺血後30分鐘內，給予allopurinol即使劑量高至200 mg/kg，亦無法減低梗塞體積。缺血前腹腔注射phenytoin在三種劑量50，100，150 mg/kg均可有效減低梗塞體積，但若缺血後30分鐘內注射phenytoin則即使劑量高達150 mg/kg亦無法減低梗塞體積。合併使用allopurinol及phenytoin，二者劑量均各為25 mg/kg（allopurinol在缺血前6小時給藥，phenytoin在缺血前三十分鐘給藥），減低腦梗塞之效果與缺血前口服allopurinol 200 mg/kg或腹腔注射phenytoin 150 mg/kg之結果相類似。這些結果顯示：（1）.二種藥物均於缺血前給藥比缺血後給藥更能降低缺血所引起之梗塞體積。（2）.兩種藥物之併用，即使在低劑量之下，亦比單一藥物之大劑量給藥對於減輕腦梗塞更有效，顯示有加強效應。

關鍵字

缺血性腦梗塞 ； 增強效應

並列摘要

The effects of combination of allopurinol, a xanthine oxidase inhibitor and possibly a free radical scavenger, and phenytoin, a membrane stabilizer, on brain infarction produced by middle cerebral artery occlusion (MCA-O) were examined in the rat. Focal ischemia was produced by occluding the right middle cerebral artery, ligating the ipsilateral common carotid artery (CCA) and clipping the contralateral CCA for 60 minutes. The left CCA clip was then released to allow reperfusion for 24 hours. Animals were then sacrificed. The brain was removed, sectioned and stained with triphenyltetrazoluim chloride (TTC). Degree of brain infarction was estimated by morphometric measurement of the infarct volume that was represented by the unstained regions. Allopurinol and phenytoin at various doses were administered individually and in combination before and after MCA-O. Our focal ischemia model resulted in a mean infarction volume of 144.94 ± 21.35 mm^3 mainly in the fronto-parietal cortex. Oral pretreatment with allopurinol at doses of 100 and 200 mg/kg (6 hours prior to ischemia) significantly reduced infarct volume; however, allopurinol administered orally 30 min after ischemia at doses up to 200 mg/kg failed to reduce the infarct volume. Intraperitoneal (i.p.) pretreatment of phenytoin at doses of 50, 100 and 150 mg/kg 30 min prior to ischemia significantly reduced the infarct volume. Phenytoin administered 30 min after ischemia failed to alleviate the infarction even at doses up to 150 mg/kg. The degree of infarction amelioration produced by the combination of allopurinol (administered 6 hr prior to ischemia) and phenytoin (administered 30 min prior to ischemia) at doses as low as 25 mg/kg of each drug was similar to that produced by 200 mg/kg of allopurinol and 150 mg/kg of phenytoin. These results indicated that pretreatment with either allopurinol or phenytoin offered better protection from ischemia-reperfusion injury of the brain than treatment after ischemia. Combination of the two drugs was more effective for the amelioration of brain infarction, even at smaller doses, suggesting a synergistic interaction between allopurinol and phenytoin in ameliorating brain infarction.

並列關鍵字

Allopurinol ； Phenytoin ； Ischemia ； Brain infarction ； Synergism