A novel neuroprotective strategy for ischemic stroke: transient mild acidosis treatment by CO2 inhalation at reperfusion
A novel neuroprotective strategy for ischemic stroke: transient mild acidosis treatment by CO2 inhalation at reperfusion
复制标题
缺血性中风的新型神经保护策略：再灌注时吸入二氧化碳治疗短暂性轻度酸中毒
DOI：
10.1038/jcbfm.2013.193
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发表时间：
2014-02-01
影响因子：
6.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
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作者：
Fan, Yan-Ying;Shen, Zhe;Chen, Zhong
酸中毒是脑缺血后处理的关键组成部分之一，近年来已成为一种内源性神经保护策略。我们开始测试再灌注时酸中毒治疗是否可以保护脑缺血/再灌注损伤。成年雄性C57 BL/6 J小鼠进行60分钟的大脑中动脉闭塞，然后再灌注24小时。在再灌注后5、50或100分钟，通过吸入10%、20%或30%CO2 5或10分钟进行酸中毒治疗。我们的研究结果表明，吸入20%CO2 5分钟后再灌注诱导最佳的神经保护作用，表现为减少梗死体积。用NaHCO 3减轻脑酸中毒显著损害了酸中毒或缺血后处理诱导的神经保护作用。酸中毒处理的原代培养皮层神经元和急性皮质纹状体脑片对氧糖剥夺/再灌注损伤的抵抗力更强。此外，酸中毒抑制缺血/再灌注诱导的细胞凋亡，caspase-3的表达，细胞色素c释放到细胞质，和线粒体通透性转换孔（mPTP）开放。在体和离体实验中，mPTP开放剂甘草酸苷均能抑制酸中毒的神经保护作用。总之，这些发现表明，短暂的轻度酸中毒治疗在再灌注保护脑缺血/再灌注损伤。这种神经保护可能至少部分地通过抑制mPTP开放和细胞凋亡来实现。
Acidosis is one of the key components in cerebral ischemic postconditioning that has emerged recently as an endogenous strategy for neuroprotection. We set out to test whether acidosis treatment at reperfusion can protect against cerebral ischemia/reperfusion injury. Adult male C57BL/6 J mice were subjected to 60-minute middle cerebral arterial occlusion followed by 24-hour reperfusion. Acidosis treatment by inhaling 10%, 20%, or 30% CO2 for 5 or 10 minutes at 5, 50, or 100 minutes after reperfusion was applied. Our results showed that inhaling 20% CO2 for 5 minutes at 5 minutes after reperfusion-induced optimal neuroprotection, as revealed by reduced infarct volume. Attenuating brain acidosis with NaHCO3 significantly compromised the acidosis or ischemic postconditioning-induced neuroprotection. Consistently, both acidosis-treated primary cultured cortical neurons and acute corticostriatal slices were more resistant to oxygen-glucose deprivation/reperfusion insult. In addition, acidosis inhibited ischemia/reperfusion-induced apoptosis, caspase-3 expression, cytochrome c release to cytoplasm, and mitochondrial permeability transition pore (mPTP) opening. The neuroprotection of acidosis was inhibited by the mPTP opener atractyloside both in vivo and in vitro. Taken together, these findings indicate that transient mild acidosis treatment at reperfusion protects against cerebral ischemia/reperfusion injury. This neuroprotection is likely achieved, at least partly, by inhibiting mPTP opening and mitochondria-dependent apoptosis.