Contrast-enhanced magnetic resonance imaging evidence for the role of astrocytic aquaporin-4 water channels in glymphatic influx and interstitial solute transport

Abstract

The present study aimed to confirm the hypothesis that aquaporin-4 water channels (AQP4) control solute transition into the brain parenchyma using image analysis of gadolinium-based contrast agents (GBCAs) dissolved in cerebrospinal fluid (CSF) on dynamic contrast-enhanced magnetic resonance imaging (dyMRI) in live rats. Ten male Wistar ST rats were included in the study. Whole-brain dyMRI was performed for approximately 120 min after intrathecal infusion of gadolinium tetraazacyclododecane tetraacetic acid (Gd-DOTA). TGN-020, a specific AQP4 inhibitor, was used to inhibit the function of AQP4 in one group of rats (TGN-020 group, n = 4). The dyMRI after Gd-DOTA infusion in the rat, who were not treated with TGN-020 (control group, n = 6) revealed marked contrast-enhancement over time based on the distribution of the GBCA in the lateral regions of the brain surface, the ventral regions, the regions adjacent to the subarachnoid space, and the deep subcortical region. In contrast, smaller signal enhancement of the same regions in the TGN-020 group indicated poor distribution of the GBCA, suggesting a physiological consequence of the AQP4 inhibition by TGN-020. In this study, a close relationship between the function of AQP4 and the solute dynamics in the CSF was revealed from the distribution pattern of GBCA visualized in dyMRI in the living rat brain by administration of AQP4-selective inhibitor. This finding suggests that AQP4 functions to drive a glymphatic influx to transition molecules dissolved in the CSF from the subarachnoid space into the extracellular space of the brain parenchyma.