Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Mol Neurosci. 2018 Mar;64(3):449-458. doi: 10.1007/s12031-018-1043-0. Epub 2018 Mar 3.
Cerebral white matter is vulnerable to ischemic condition. However, no effective treatment to alleviate or restore the myelin damage caused by chronic cerebral hypoperfusion has been found. Na-K-Cl cotransporter 1 (NKCC1), a Na-K-Cl cotransporter widely expressed in the central nervous system (CNS), involves in regulation of cell swelling, EAA release, cell apoptosis, and proliferation. Nevertheless, the role of NKCC1 in chronic hypoperfusion-induced white matter lesions (WMLs) has not been explored. Here, mice subjected to bilateral common carotid artery stenosis (BCAS) were used as model of chronic cerebral hypoperfusion; density of progenitor cells of oligodendrocyte (OPCs), oligodendrocytes (OLs), astrocytes, and microglia was assessed by immunofluorescent staining and Western blot analysis; working memory was examined by eight-arm radial maze test; expression of MAPK signaling pathway was determined by Western blot analysis. After BCAS, white matter integrity disruption and working memory impairment were observed. NKCC1 inhibition by bumetanide administration enhanced OPC proliferation, attenuated chronic hypoperfusion-induced white matter damage, and promoted recovery of neurological function. However, NKCC1 inhibition caused no significant change in the densities of GFAP- and Iba-1-positive cells in the corpus callosum. Bumetanide administration significantly increased the expression of p-ERK and decreased the expression of p-JNK and p-p38 in comparison to vehicle-BCAS groups. In conclusion, NKCC1 inhibition might significantly ameliorate chronic cerebral hypoperfusion-induced WMLs and cognitive impairment by enhancing progenitor cells of oligodendrocyte proliferation, and this protective function of bumetanide might be mediated by modulation of the MAPK signaling pathway.
脑白质容易受到缺血性损伤。然而，目前尚未发现有效的治疗方法来缓解或修复慢性脑低灌注引起的髓鞘损伤。钠钾氯共转运蛋白 1（NKCC1）是一种在中枢神经系统（CNS）中广泛表达的钠钾氯共转运蛋白，参与细胞肿胀、EAA 释放、细胞凋亡和增殖的调节。然而，NKCC1 在慢性低灌注诱导的脑白质病变（WML）中的作用尚未被探索。在这里，我们使用双侧颈总动脉狭窄（BCAS）小鼠作为慢性脑低灌注模型；通过免疫荧光染色和 Western blot 分析评估少突胶质细胞前体细胞（OPCs）、少突胶质细胞（OLs）、星形胶质细胞和小胶质细胞的密度；通过八臂放射迷宫试验检测工作记忆；通过 Western blot 分析检测 MAPK 信号通路的表达。BCAS 后，观察到白质完整性破坏和工作记忆障碍。布美他尼抑制 NKCC1 可增强 OPC 增殖，减轻慢性低灌注引起的白质损伤，并促进神经功能恢复。然而，NKCC1 抑制对胼胝体中 GFAP 和 Iba-1 阳性细胞的密度没有显著影响。与vehicle-BCAS 组相比，布美他尼给药组 p-ERK 的表达显著增加，而 p-JNK 和 p-p38 的表达显著降低。总之，NKCC1 抑制可能通过增强少突胶质细胞前体细胞的增殖来显著改善慢性脑低灌注引起的 WML 和认知障碍，而布美他尼的这种保护作用可能是通过调节 MAPK 信号通路介导的。
