Folbergrová J, Zhao Q, Katsura K, Siesjö B K
Laboratory for Experimental Brain Research, Lund University Hospital, Sweden.
Proc Natl Acad Sci U S A. 1995 May 23;92(11):5057-61. doi: 10.1073/pnas.92.11.5057.
Recent results have demonstrated that the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) reduces infarct size due to middle cerebral artery occlusion (MCAO), even when given after ischemia. The objective of the present study was to explore whether PBN influences recovery of energy metabolism. MCAO of 2-hr duration was induced in rats by an intraluminal filament technique. Brains were frozen in situ at the end of ischemia and after 1, 2, and 4 hr of recirculation. PBN was given 1 hr after recirculation. Neocortical focal and perifocal ("penumbra") areas were sampled for analyses of phosphocreatine (PCr), creatine, ATP, ADP, AMP, glycogen, glucose, and lactate. The penumbra showed a moderate-to-marked decrease and the focus showed a marked decrease in PCr and ATP concentrations, a decline in the sum of adenine nucleotides, near-depletion of glycogen, and an increase in lactate concentration after 2 hr of ischemia. Recirculation for 1 hr led to only a partial recovery of energy state, with little further improvement after 2 hr and signs of secondary deterioration after 4 hr, particularly in the focus. After 4 hr of recirculation, PBN-treated animals showed pronounced recovery of energy state, with ATP and lactate contents in both focus and penumbra approaching normal values. Although an effect of PBN on mitochondria cannot be excluded, the results suggest that PBN acts by preventing a gradual compromise of microcirculation. The results justify a reevaluation of current views on the pathophysiology of focal ischemic damage and suggest that a therapeutic window of many hours exists in stroke.
近期研究结果表明，自旋捕捉剂N-叔丁基-α-苯基硝酮（PBN）可减小大脑中动脉闭塞（MCAO）所致的梗死灶大小，即便在缺血后给药也有此效果。本研究的目的是探究PBN是否会影响能量代谢的恢复。采用腔内丝线技术在大鼠中诱导2小时的MCAO。在缺血结束时以及再灌注1、2和4小时后将大脑原位冷冻。再灌注1小时后给予PBN。采集新皮质局灶性和局灶周围（“半暗带”）区域样本，用于分析磷酸肌酸（PCr）、肌酸、三磷酸腺苷（ATP）、二磷酸腺苷（ADP）、一磷酸腺苷（AMP）、糖原、葡萄糖和乳酸。缺血2小时后，半暗带显示中度至显著降低，局灶性区域显示PCr和ATP浓度显著降低，腺嘌呤核苷酸总和下降，糖原近乎耗尽，乳酸浓度升高。再灌注1小时仅导致能量状态部分恢复，2小时后改善甚微，4小时后出现继发性恶化迹象，尤其是在局灶性区域。再灌注4小时后，接受PBN治疗的动物能量状态明显恢复，局灶性区域和半暗带的ATP和乳酸含量均接近正常值。尽管不能排除PBN对线粒体的作用，但结果表明PBN通过防止微循环逐渐受损而发挥作用。这些结果证明有必要重新评估当前关于局灶性缺血性损伤病理生理学的观点，并表明中风存在数小时的治疗窗。
