Bokesch P M, Seirafi P A, Warner K G, Marchand J E, Kream R M, Trapp B
Department of Cardiothoracic Anesthesia, The Cleveland Clinic Foundation, Ohio 44195, USA.
Anesthesiology. 1998 Oct;89(4):961-8. doi: 10.1097/00000542-199810000-00021.
This study determined the induction profiles of immediate-early genes in the ovine brain after cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA), and the effects of the noncompetitive N-methyl-D-aspartate antagonist, aptiganel, on immediate-early gene expression, neuronal necrosis, and functional outcome.
Cannulas were inserted into isoflurane-anesthetized neonatal lambs undergoing CPB. One group received 2.5 mg/kg intravenous aptiganel. Animals underwent 90 or 120 min of HCA at 16 degrees C, were rewarmed to 38 degrees C, and were weaned from CPB. One hour after CPB was discontinued, brain perfusion was fixed and removed for immunohistochemical analysis in one half of the animals. The other half survived 2 or 3 days before their brains were evaluated for neuronal degeneration. Data were analyzed using analysis of variance; P < 0.05 was considered significant.
Cardiopulmonary bypass and HCA differentially induced c-Jun and Fos proteins in the hippocampal formation, with c-Jun expression increasing with the duration of HCA, whereas Fos protein expressions were greatest after 90 min of HCA. The c-Jun protein was expressed in all neurons except the dentate gyrus. The Fos proteins were expressed in all neurons, including the dentate gyrus. Neuronal necrosis was observed in CA1 (73%) and CA3 (29%) neurons but not in the dentate gyrus after 120 min of HCA. Aptiganel completely inhibited c-Jun expression (P < 0.001) but not Fos, improved functional outcome, and attenuated neuronal necrosis (P < 0.05).
The c-Jun and c-Fos proteins are expressed differentially in hippocampal neurons after CPB and HCA. Expression of c-Jun is associated with neuronal necrosis, whereas Fos protein expression is associated with survival. Aptiganel inhibits c-Jun expression, attenuates neuronal necrosis, and improves outcome.
本研究确定了体外循环（CPB）和低温循环停搏（HCA）后绵羊大脑中即刻早期基因的诱导模式，以及非竞争性N-甲基-D-天冬氨酸拮抗剂阿替加奈对即刻早期基因表达、神经元坏死和功能转归的影响。
将插管插入接受CPB的异氟烷麻醉新生羔羊体内。一组静脉注射2.5mg/kg阿替加奈。动物在16℃下进行90或120分钟的HCA，复温至38℃，并脱离CPB。CPB停止1小时后，对一半动物进行脑灌注固定并取出用于免疫组化分析。另一半存活2或3天，然后对其大脑进行神经元变性评估。数据采用方差分析进行分析；P<0.05被认为具有统计学意义。
CPB和HCA在海马结构中差异诱导c-Jun和Fos蛋白，c-Jun表达随HCA持续时间增加，而Fos蛋白表达在HCA 90分钟后最高。c-Jun蛋白在除齿状回外的所有神经元中表达。Fos蛋白在包括齿状回在内的所有神经元中表达。HCA 120分钟后，在CA1（73%）和CA3（29%）神经元中观察到神经元坏死，但在齿状回中未观察到。阿替加奈完全抑制c-Jun表达（P<0.001）但不抑制Fos，改善功能转归，并减轻神经元坏死（P<0.05）。
CPB和HCA后，c-Jun和c-Fos蛋白在海马神经元中的表达存在差异。c-Jun的表达与神经元坏死相关，而Fos蛋白表达与存活相关。阿替加奈抑制c-Jun表达，减轻神经元坏死，并改善转归。
