Impaired Glymphatic Transport Kinetics Following Induced Acute Ischemic Brain Edema in a Mouse pMCAO Model

Jianying Zhang; Hongchen Zhao; Yang Xue; Yiqi Liu; Guohang Fan; He Wang; Qiang Dong; Wenjie Cao

doi:10.3389/fneur.2022.860255

Impaired Glymphatic Transport Kinetics Following Induced Acute Ischemic Brain Edema in a Mouse pMCAO Model

Front Neurol. 2022 Mar 17:13:860255. doi: 10.3389/fneur.2022.860255. eCollection 2022.

Authors

Jianying Zhang¹, Hongchen Zhao¹, Yang Xue¹, Yiqi Liu¹, Guohang Fan¹, He Wang², Qiang Dong^{1

3

4}, Wenjie Cao¹

Affiliations

¹ Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
² The Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
³ State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
⁴ National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.

Abstract

Background: Cerebral edema forms immediately after blood flow interruption in ischemic stroke, which largely increased the death and disability. The glymphatic (glial-lymphatic) pathway is a major regulator of the brain liquid dynamics and homeostasis. This study aimed to investigate the transport kinetics of the glymphatic system after the appearance of ischemic edema.

Methods: In this study, a coated filament was attached to the left middle cerebral artery (MCA) of mice to establish a mouse model of permanent middle cerebral artery occlusion with an intact blood-brain barrier (BBB). The glymphatic function was then quantified using contrast-enhanced MRI (11.7T) by employing an injection of gadobenate dimeglumine (BOPTA-Gd) into the cisterna magna of mice. We then evaluated the expression and polarization of aquaporin-4 (AQP4) as a proxy for the physiological state of the glymphatic system.

Results: Our results revealed a positive correlation between the signal intensity in T1-weighted images and the corresponding apparent diffusion coefficient (ADC) values in the cortex, striatum, and periventricular zone, suggesting that impaired glymphatic transport kinetics in these regions is correlated to the cytotoxic edema induced by the occlusion of MCA. Furthermore, the increased depolarization of AQP4 in the parenchyma perivascular space (PVS) was consistent with glymphatic failure following the induced early cerebral ischemic edema.

Conclusions: Glymphatic transport kinetics were suppressed between the onset of cytotoxic edema and the disruption of the BBB, which correlated with the diminishing ADC values that vary based on edema progression, and is associated with depolarization of AQP4 in the parenchyma PVSs.

Keywords: aquaporin-4; cerebral ischemic edema; glymphatic; magnetic resonance imaging; polarization.