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Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2021-08-28 , DOI: 10.1186/s12974-021-02234-8
Qian Liu 1, 2, 3 , Mohammad Iqbal H Bhuiyan 2, 3 , Ruijia Liu 2, 3 , Shanshan Song 2, 3 , Gulnaz Begum 2, 3 , Cullen B Young 2, 3 , Lesley M Foley 4 , Fenghua Chen 2 , T Kevin Hitchens 4, 5 , Guodong Cao 2, 6 , Ansuman Chattopadhyay 7 , Li He 1 , Dandan Sun 2, 3, 6
Affiliation  

Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na+/H+ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.

中文翻译:

减轻血管狭窄引起的星形胶质细胞增生可保持白质完整性和认知功能

慢性脑灌注不足 (CCH) 导致白质损伤和认知障碍,其中星形胶质细胞增生是主要病理。然而,潜在的细胞机制并没有得到很好的定义。活性星形胶质细胞中 Na+/H+ 交换器-1 (NHE1) 的激活导致星形胶质细胞肥大和肿胀。在这项研究中,我们在双侧颈动脉狭窄 (BCAS) 的小鼠 CCH 模型中检查了 NHE1 蛋白在星形胶质细胞增生、白质脱髓鞘和认知功能中的作用。对接受载体或选择性 NHE1 抑制剂 HOE642 的 Sham、BCAS 或 BCAS 小鼠进行 28 天的局部脑血流变化和行为表现的监测。随后进行离体 MRI-DTI 以检测脑损伤和脱髓鞘。通过免疫荧光染色进一步检查星形胶质细胞增生和脱髓鞘。用大量 RNA 测序和 RT-qPCR 分析星形胶质细胞的转录谱。在 BCAS 小鼠中检测到慢性脑血流减少和空间工作记忆缺陷,同时在 MRI DTI 分析中,胼胝体、外囊和海马的平均分数各向异性 (FA) 值显着降低。与假控制小鼠相比,BCAS 小鼠表现出脱髓鞘和轴突损伤,并增加了 GFAP+ 星形胶质细胞和 Iba1+ 小胶质细胞。NHE1 蛋白及其抑制剂 HOE642 的药理抑制作用可防止 BCAS 诱导的神经胶质增生、白质束和海马体的损伤,并显着改善认知能力。转录组和免疫染色分析进一步表明,NHE1 抑制特异性地减弱了促炎途径和 NADPH 氧化酶活化。
更新日期:2021-08-29
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