Brambrink Ansgar M, Koerner Ines P, Diehl Kathrin, Strobel Georg, Noppens Ruediger, Kempski Oliver
Department of Anesthesiology and Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University, Mainz, Germany.
Anesthesiology. 2006 Jun;104(6):1208-15. doi: 10.1097/00000542-200606000-00016.
Cerebral ischemic tolerance can be induced by a variety of noxious stimuli, but no clinically applicable regimen for preconditioning has been described. Therefore, the authors tested the ability of a pharmacologic preconditioning strategy using the well-known macrolide antibiotic erythromycin to induce tolerance against transient global cerebral ischemia in vivo. They also investigated whether tolerance induction by erythromycin involves transcriptional and translational changes of cerebral B-cell leukemia/lymphoma-2 (bcl-2) expression.
Male Wistar rats were treated with erythromycin (25 mg/kg intramuscularly) or vehicle and subjected to 15 min of transient global cerebral ischemia 6, 12, or 24 h after pretreatment. Neurologic deficit was evaluated once daily, and neuronal cell survival was assessed after 7 days of reperfusion. Additional animals were similarly pretreated, and cerebral bcl-2 messenger RNA (mRNA) and protein expression was analyzed 6 and 24 h later.
Erythromycin improved postischemic neuronal survival in hippocampal CA1 and CA3 sectors and reduced functional deficit, with 12 h being the most efficient pretreatment interval. Bcl-2 mRNA in hippocampus was transiently up-regulated 6 h after erythromycin, but neuronal Bcl-2 protein remained unchanged.
Erythromycin can induce cerebral ischemic tolerance in vivo (pharmacologic preconditioning), suggesting a potential clinical strategy of preemptive neuroprotection. Changes in bcl-2 expression after erythromycin were small and transient. The induction of bcl-2-related pathways, although important for other preconditioning regimens, may therefore be less relevant for the neuroprotective effects of pharmacologic preconditioning using erythromycin.
多种有害刺激可诱导脑缺血耐受，但尚未有可用于临床的预处理方案。因此，作者测试了使用著名的大环内酯类抗生素红霉素的药物预处理策略在体内诱导对短暂性全脑缺血耐受的能力。他们还研究了红霉素诱导的耐受是否涉及脑B细胞淋巴瘤/白血病-2（bcl-2）表达的转录和翻译变化。
雄性Wistar大鼠接受红霉素（25mg/kg肌肉注射）或赋形剂处理，并在预处理后6、12或24小时接受15分钟的短暂性全脑缺血。每天评估一次神经功能缺损，并在再灌注7天后评估神经元细胞存活情况。对其他动物进行类似的预处理，并在6和24小时后分析脑bcl-2信使核糖核酸（mRNA）和蛋白质表达。
红霉素改善了海马CA1和CA3区缺血后神经元的存活，并减少了功能缺损，12小时是最有效的预处理间隔。红霉素处理6小时后，海马中的bcl-2 mRNA短暂上调，但神经元Bcl-2蛋白保持不变。
红霉素可在体内诱导脑缺血耐受（药物预处理），提示一种潜在的临床抢先神经保护策略。红霉素处理后bcl-2表达的变化较小且短暂。因此，尽管bcl-2相关途径的诱导对其他预处理方案很重要，但可能与使用红霉素的药物预处理的神经保护作用相关性较小。
