Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion
Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion
复制标题
地高辛改善慢性脑灌注不足小鼠模型中的类淋巴运输和认知障碍。
DOI：
10.1007/s12264-021-00772-y
复制
发表时间：
2021-10-27
影响因子：
5.6
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Cao, Jie;Yao, Di;Wang, Wei
淋巴系统在维持大脑稳态中起着关键作用。由小血管病变或颈动脉狭窄引起的慢性脑灌注不足可导致脑血管代谢紊乱，最终表现为脑白质损伤和认知功能障碍。然而，淋巴系统是否作为脑灌注不足时白质损伤和认知能力下降的潜在治疗靶点仍不清楚。本实验建立双侧颈总动脉狭窄小鼠慢性脑灌注不足模型。我们发现低灌注模型与显著的白质损伤和初始认知障碍相关，并伴有淋巴系统功能受损。淋巴功能障碍与脑灌注改变和水通道蛋白4极化丧失有关。地高辛的治疗挽救了类淋巴转运、白质结构和认知功能的改变。用AQP4抑制剂TGN-020抑制淋巴功能可消除地高辛对低灌注损伤的保护作用。我们的研究为慢性脑灌注不足后的血流动力学、淋巴转运、白质损伤和认知变化之间的关系提供了新的见解。
The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.