Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via protecting astrocytic mitochondria
Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via protecting astrocytic mitochondria
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Resolvin D1 通过保护星形胶质细胞线粒体来改善创伤性脑损伤后的认知障碍。
DOI：
10.1111/jnc.14962
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发表时间：
2020-01-29
影响因子：
4.7
通讯作者：
Zhang, Zhi-Yuan
中科院分区：
文献类型：
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作者：
Ren, Yi-Zhi;Zhang, Ben-Zheng;Zhang, Zhi-Yuan
认知障碍是创伤性脑损伤（TBI）后最常见和最具破坏性的神经精神后遗症之一，海马神经元存活在这一病理过程中起着因果作用。Resolvin D1（RvD 1）是一种重要的内源性特异性促消退介质，对线粒体具有保护作用。这表明RvD 1可能在抑制神经炎症的同时保护星形胶质细胞线粒体，发挥进一步的神经保护作用。使用受控皮质撞击（CCI）装置进行TBI的C57 BL/6小鼠用于体内实验。培养的原代小鼠星形胶质细胞和N2 a小鼠神经母细胞瘤细胞系用于体外实验。在TBI小鼠中，RvD 1显着改善认知障碍，抑制神经胶质增生，减轻海马神经元丢失。为了探索这种活性的机制，我们证实了RvD 1可以诱导更高水平的线粒体自噬，以通过激活星形胶质细胞中的ALX 4/FPR 2受体来去除受损的线粒体并消除额外的线粒体衍生的活性氧（mitoROS）。在体外模型中，我们进一步证实了RvD 1可以保护星形胶质细胞中的线粒体形态和膜电位，从而提高神经元的存活。同时，RvD 1也被证明增加脑源性神经营养因子（BDNF）和谷氨酸天冬氨酸转运蛋白（GLAST）在海马TBI后的表达，这表明一个可能的方式，RvD 1增加星形胶质细胞的支持功能。这些发现表明，RvD 1可能是一种有效的治疗选择，通过控制神经炎症和保护星形胶质细胞线粒体来改善TBI后的认知障碍。
Cognitive impairment is one of the most common and devastating neuropsychiatric sequelae after traumatic brain injury (TBI), and hippocampal neuronal survival plays a causal role in this pathological process. Resolvin D1 (RvD1), an important endogenous specialized pro-resolving mediator, has recently been reported to exert a potent protective effect on mitochondria. This suggests that RvD1 may suppress neuroinflammation and protect astrocytic mitochondria at the same time to play further neuroprotective roles. C57BL/6 mice subjected to TBI using a controlled cortical impact (CCI) device were used for in vivo experiments. Cultured primary mouse astrocytes and an N2a mouse neuroblastoma cell line were used for in vitro experiments. In TBI mice, RvD1 significantly ameliorated cognitive impairment, suppressed gliosis and alleviated neuronal loss in the hippocampus. To explore the mechanism underlying this activity, we verified that RvD1 can induce a higher level of mitophagy to remove damaged mitochondria and eliminate extra mitochondria-derived reactive oxygen species (mitoROS) by activating ALX4/FPR2 receptors in astrocytes. In an in vitro model, we further confirmed that RvD1 can protect mitochondrial morphology and membrane potential in astrocytes and thereby enhance the survival of neurons. Meanwhile, RvD1 was also shown to increase the expression of brain-derived neurotrophic factor (BDNF) and glutamate aspartate transporter (GLAST) in the hippocampus following TBI, which indicates a possible way by which RvD1 increases the supportive function of astrocytes. These findings suggest that RvD1 may be a potent therapeutic option for ameliorating cognitive impairment following TBI by controlling neuroinflammation and protecting astrocytic mitochondria.