Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function
Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function
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L-OPA1 的恢复通过抑制神经元凋亡和保护线粒体功能减轻大鼠急性缺血性中风损伤
DOI：
10.1016/j.redox.2020.101503
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发表时间：
2020-07-01
期刊：
影响因子：
11.4
通讯作者：
Chen, Hongbin
中科院分区：
文献类型：
--
作者：
Lai, Yongxing;Lin, Peiqiang;Chen, Hongbin
背景：缺血性脑卒中可引起线粒体形态和功能的改变。视神经萎缩1（optic atrophy 1，OPA 1）作为线粒体中的一个调控基因，在调节线粒体动力学及其他相关功能中起着关键作用。然而，其在脑缺血相关疾病中的作用几乎不为人所知。研究方法：分别用编码OPA 1-v1 S1和OPA 1-v1慢病毒转染原代培养的大鼠皮层神经元，然后进行2 h氧糖剥夺（OGD）和随后的再氧合（OGD/R）。成年雄性SD大鼠接受颅内注射AAV-OPA 1-v1 S1，并经历短暂大脑中动脉闭塞（tMCAO）90分钟，随后再灌注。通过体外和体内实验检测OPA 1的表达和功能。结果：脑缺血/再灌注损伤后，无论在体外还是在体内，OPA 1都被过度切割。在OGD/R条件下，与LV-OPA 1-v1处理组相比，OPA 1-v1 S1的表达能有效恢复L-OPA 1水平，减轻神经元死亡和线粒体形态学损伤。同时，OPA 1-v1 S1的表达可明显改善脑缺血再灌注所致的运动功能损害，减少脑梗死体积、神经元凋亡、线粒体生物能学缺陷、氧化应激，恢复线粒体嵴形态和长度。保护缺血大鼠线粒体的完整性，增强线粒体DNA含量和线粒体生物合成因子的表达。释义：我们的研究结果表明，L-OPA 1的稳定化通过减少神经元凋亡和保护线粒体功能来保护缺血性脑，表明其作为中风预防和治疗的有希望的治疗靶点的意义。
Background: Ischemic stroke can induce changes in mitochondrial morphology and function. As a regulatory gene in mitochondria, optic atrophy 1 (OPA1) plays a pivotal role in the regulation of mitochondrial dynamics and other related functions. However, its roles in cerebral ischemia-related conditions are barely understood. Methods: Cultured rat primary cortical neurons were respectively transfected with OPA1-v1 S1-encoding and OPA1-v1-encoding lentivirus before exposure to 2-h oxygen-glucose deprivation (OGD) and subsequent reox-ygenation (OGD/R). Adult male SD rats received an intracranial injection of AAV-OPA1-v1 S1 and were sub-jected to 90 min of transient middle cerebral artery occlusion (tMCAO) followed by reperfusion. OPA1 ex-pression and function were detected by in vitro and in vivo assays. Results: OPA1 was excessively cleaved after cerebral ischemia/reperfusion injury, both in vitro and in vivo. Under OGD/R condition, compared with that of the LV-OPA1-v1-treated group, the expression of OPA1-v1 S1 efficiently restored L-OPA1 level and alleviated neuronal death and mitochondrial morphological damage. Meanwhile, the expression of OPA1-v1 S1 markedly improved cerebral ischemia/reperfusion-induced motor function damage, attenuated brain infarct volume, neuronal apoptosis, mitochondrial bioenergetics deficits, oxidative stress, and restored the morphology of mitochondrial cristae and mitochondrial length. It also pre-served the mitochondrial integrity and reinforced the mtDNA content and expression of mitochondrial bio-genesis factors in ischemic rats. Interpretation: Our results demonstrate that the stabilization of L-OPA1 protects ischemic brains by reducing neuronal apoptosis and preserving mitochondrial function, suggesting its significance as a promising therapeutic target for stroke prevention and treatment.