Impediment of Cerebrospinal Fluid Drainage Through Glymphatic System in Glioma.

Dan Xu,Jie Zhou,Wenbo Sun,Hao Mei,Huan Li,Haibo Xu

doi:10.3389/fonc.2021.790821

Dan Xu, Jie Zhou + Show 4 more

Open Access

https://doi.org/10.3389/fonc.2021.790821

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Abstract

BackgroundCerebrospinal fluid (CSF) plays an important role in maintaining tissue homeostasis in the central nervous system. In 2012, the new CSF outflow pathway, “the glymphatic system,” was discovered. The glymphatic system mediates CSF and interstitial fluid exchange through the perivascular pathway, which eliminates harmful solutes in the brain parenchyma. In recent studies, the importance of the glymphatic system has been demonstrated in healthy and neurodegenerative disease brains. However, there is limited research on the function of the CSF in brain tumors. Intracranial hypertension caused by glioma can affect CSF drainage, which impacts the delivery of chemotherapy drugs via intrathecal injection. This study focused on changes in the glymphatic system and the role of aquaporin 4 (AQP4) in glymphatic transport in glioma.MethodsIn glioma-bearing rats, the effect of tracer infusion on the intracranial pressure (ICP) was evaluated using an ICP microsensor. In vivo magnetic resonance imaging and ex vivo bright field were used to monitor CSF tracer distribution after cisterna magna injection. AQP4 expression was quantitatively detected, and AQP4 in the astrocytes around the vessels was observed using immunofluorescence.ResultsThe ICP of the tumor group was higher than that of the control group and the infusion rate of 2 µl/min did not affect ICP. In vivo and ex vivo imaging showed that the circulation of CSF tracers was significantly impaired in the tumor. High-power confocal microscopy revealed that, in the tumor, the surrounding of AQP4 by Evans Blue was decreased. In both tumor and contralateral areas, data indicated that the number of cluster designation 34 (CD34+) alpha-smooth muscle actin (α-SMA−) veins were more than that of CD34+α-SMA+ arteries. Moreover, in the tumor area, AQP4 in the astrocytes around the vessels was decreased.ConclusionsThese findings indicate that the para-arterial influx of subarachnoid CSF is limited in glioma, especially in those with reduced levels of the fundamental protein AQP4. Our results provide evidence toward a potential new treatment method for glioma in the future.

Highlights

Cerebrospinal fluid (CSF) is produced by the choroid plexus in the ventricular system, which is formed by four interconnected cavities
In glioma followed by the vasogenic brain edema model, aquaporin 4 (AQP4)-null mice showed a significantly greater increase in water in the brain and intracranial pressure (ICP) than that in wildtype mice [16, 21, 22]. These findings suggest that the transmolecular water transport mediated by AQP4 plays a crucial role in the outflow of CSF
To prevent neurotoxicity from a large amount of gadolinium accumulating in the brain in a short time and intracranial hypertension caused by the rapid infusion rate into the cisterna magna [42], we measured ICP at different infusion rates to ensure a safe infusion rate

Summary

Introduction

Cerebrospinal fluid (CSF) is produced by the choroid plexus in the ventricular system, which is formed by four interconnected cavities (two lateral ventricles and the third and fourth ventricles). To maintain tissue homeostasis and its normal function, the CSF is thought to play a role in the clearance of solutes from the brain. The glymphatic system is defined as a brain-wide perivascular pathway driven by astrocytic aquaporin 4 (AQP4). It plays an important role in clearing the interstitial solutes in the brain parenchyma and involves the para-arterial influx of subarachnoid CSF into the brain interstitium, the exchange of CSF with interstitial fluid (ISF), followed by the para-venous efflux of ISF. Cerebrospinal fluid (CSF) plays an important role in maintaining tissue homeostasis in the central nervous system. The glymphatic system mediates CSF and interstitial fluid exchange through the perivascular pathway, which eliminates harmful solutes in the brain parenchyma. This study focused on changes in the glymphatic system and the role of aquaporin 4 (AQP4) in glymphatic transport in glioma

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