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Inhibition of RhoA/ROCK Pathway in the Early Stage of Hypoxia Ameliorates Depression in Mice via Protecting Myelin Sheath.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-15 , DOI: 10.1021/acschemneuro.0c00352 Baichuan Li 1 , Yang Xu 1 , Yong Quan 2 , Qiyan Cai 1 , Yifan Le 1 , Teng Ma 1 , Zhi Liu 1 , Guangyan Wu 2 , Fei Wang 1 , Chuncha Bao 2 , Hongli Li 1, 2
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-15 , DOI: 10.1021/acschemneuro.0c00352 Baichuan Li 1 , Yang Xu 1 , Yong Quan 2 , Qiyan Cai 1 , Yifan Le 1 , Teng Ma 1 , Zhi Liu 1 , Guangyan Wu 2 , Fei Wang 1 , Chuncha Bao 2 , Hongli Li 1, 2
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Neuroplasticity and connectivity in the central nervous system (CNS) are easily damaged after hypoxia. Long-term exposure to an anoxic environment can lead to neuropsychiatric symptoms and increases the likelihood of depression. Demyelination is an important lesion of CNS injury that may occur in depression. Previous studies have found that the RhoA/ROCK pathway is upregulated in neuropsychiatric disorders such as multiple sclerosis, stroke, and neurodegenerative diseases. Therefore, the chief aim of this study is to explore the regulatory role of the RhoA/ROCK pathway in the development of depression after hypoxia by behavioral tests, Western blotting, immunostaining as well as electron microscopy. Results showed that HIF-1α, S100β, RhoA/ROCK, and immobility time in FST were increased, sucrose water preference ratio in SPT was decreased, and the aberrant activity of neurocyte and demyelination occurred after hypoxia. After the administration of Y-27632 and fluoxetine in hypoxia, these alterations were improved. Lingo1, a negative regulatory factor, was also overexpressed after hypoxia and its expression was decreased when the pathway blocked. However, fluoxetine had no effect on the expression of Lingo1. Then, we demonstrated that demyelination was associated with failures of oligodendrocyte precursor cell proliferation and differentiation and increased apoptosis of oligodendrocytes. Collectively, our data indicate that the RhoA/ROCK pathway plays a vital role in the initial depression during hypoxia. Blocking this pathway in the early stage of hypoxia can enhance the effectiveness of antidepressants, rescue myelin damage, and reduce the expression of the negative regulatory protein of myelination. The findings provide new insight into the prophylaxis and treatment of depression.
中文翻译：
低氧早期抑制RhoA / ROCK途径可通过保护髓鞘来减轻小鼠的抑郁感。
缺氧后，中枢神经系统（CNS）的神经可塑性和连通性容易受损。长期暴露于缺氧环境会导致神经精神症状并增加患抑郁症的可能性。脱髓鞘是抑郁症中可能发生的CNS损伤的重要病变。先前的研究发现，在多发性硬化症，中风和神经退行性疾病等神经精神疾病中，RhoA / ROCK通路上调。因此，本研究的主要目的是通过行为测试，Western印迹，免疫染色以及电子显微镜研究RhoA / ROCK通路在缺氧后抑郁症发展中的调控作用。结果表明，FST中的HIF-1α，S100β，RhoA / ROCK和固定时间增加，SPT中的蔗糖水偏爱率降低，缺氧后发生神经细胞异常活动和脱髓鞘。在缺氧状态下施用Y-27632和氟西汀后，这些改变得到改善。缺氧后，Lingo1，一种负调节因子，也被过表达，当通路被阻断时，其表达降低。但是，氟西汀对Lingo1的表达没有影响。然后，我们证明脱髓鞘与少突胶质前体细胞的增殖和分化失败以及少突胶质细胞的凋亡增加有关。总体而言，我们的数据表明RhoA / ROCK通路在缺氧期间的初始抑郁中起着至关重要的作用。在缺氧的早期阶段阻断该途径可以增强抗抑郁药的有效性，挽救髓磷脂的损伤，并降低髓鞘形成的负调控蛋白的表达。这些发现为预防和治疗抑郁症提供了新的见识。
更新日期：2020-09-02
中文翻译：
低氧早期抑制RhoA / ROCK途径可通过保护髓鞘来减轻小鼠的抑郁感。
缺氧后，中枢神经系统（CNS）的神经可塑性和连通性容易受损。长期暴露于缺氧环境会导致神经精神症状并增加患抑郁症的可能性。脱髓鞘是抑郁症中可能发生的CNS损伤的重要病变。先前的研究发现，在多发性硬化症，中风和神经退行性疾病等神经精神疾病中，RhoA / ROCK通路上调。因此，本研究的主要目的是通过行为测试，Western印迹，免疫染色以及电子显微镜研究RhoA / ROCK通路在缺氧后抑郁症发展中的调控作用。结果表明，FST中的HIF-1α，S100β，RhoA / ROCK和固定时间增加，SPT中的蔗糖水偏爱率降低，缺氧后发生神经细胞异常活动和脱髓鞘。在缺氧状态下施用Y-27632和氟西汀后，这些改变得到改善。缺氧后，Lingo1，一种负调节因子，也被过表达，当通路被阻断时，其表达降低。但是，氟西汀对Lingo1的表达没有影响。然后，我们证明脱髓鞘与少突胶质前体细胞的增殖和分化失败以及少突胶质细胞的凋亡增加有关。总体而言，我们的数据表明RhoA / ROCK通路在缺氧期间的初始抑郁中起着至关重要的作用。在缺氧的早期阶段阻断该途径可以增强抗抑郁药的有效性，挽救髓磷脂的损伤，并降低髓鞘形成的负调控蛋白的表达。这些发现为预防和治疗抑郁症提供了新的见识。
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