The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

 So your doctor needs to have EXACT STROKE PROTOCOLS for measuring and assuring the correct glymphatic levels.

• glymphatic system (7 posts to October 2016)

The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment

Tao Lv¹, Bing Zhao¹, Qin Hu^2* and Xiaohua Zhang^1*

• ¹Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
• ²Central Laboratory, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

The glymphatic system (GS) is a novel defined brain-wide perivascular transit network between cerebrospinal fluid (CSF) and interstitial solutes that facilitates the clearance of brain metabolic wastes. The complicated network of the GS consists of the periarterial CSF influx pathway, astrocytes-mediated convective transport of fluid and solutes supported by AQP4 water channels, and perivenous efflux pathway. Recent researches indicate that the GS dysfunction is associated with various neurological disorders, including traumatic brain injury, hydrocephalus, epilepsy, migraine, and Alzheimer’s disease (AD). Meanwhile, the GS also plays a pivotal role in the pathophysiological process of stroke, including brain edema, blood–brain barrier (BBB) disruption, immune cell infiltration, neuroinflammation, and neuronal apoptosis. In this review, we illustrated the key anatomical structures of the GS, the relationship between the GS and the meningeal lymphatic system, the interaction between the GS and the BBB, and the crosstalk between astrocytes and other GS cellular components. In addition, we contributed to the current knowledge about the role of the GS in the pathology of stroke and the role of AQP4 in stroke. We further discussed the potential use of the GS in early risk assessment, diagnostics, prognostics, and therapeutics of stroke.

Introduction

Clearing the metabolic wastes and maintaining the fluid homeostasis are important for brain function. In most organs, the lymphatic network is responsible for the wastes clearance and fluid drainage (Ikomi et al., 2012). However, a hallmark of the brain is the absence of typical lymphatic structures. Due to the presence of blood–brain barrier (BBB), the movement of solutes and ions in the brain is strictly restricted. Cerebrospinal fluid (CSF) has been considered to be important for the exchange of water-soluble metabolites; however, its mechanisms remain largely unknown. Iliff et al. (2012) reported the existence of the glymphatic system (GS) in the central nervous system (CNS), which is an alternative clearance system located in the perivascular space and aquaporin-4 (AQP4) dependent (Iliff et al., 2012). Emerging evidence from human studies and rodent models suggests that the GS is crucial for maintaining brain health, and dysfunction of GS is closely associated with various neurological disorders, including aging, neurodegeneration, and acute brain injury (de Leon et al., 2017; Ringstad et al., 2017). In parallel, the meningeal lymphatic vessels were discovered and demonstrated to participate in solutes transport and in immune surveillance (Aspelund et al., 2015; Louveau et al., 2015, 2016; Antila and Karaman, 2017).

Stroke, a major cause of death and disability, affects over 800,000 individuals annually (Coutts, 2017). It has been well-recognized that the GS plays a crucial role in the pathophysiology of stroke, including brain edema, blood–brain barrier (BBB) disruption, immune cell infiltration, neuroinflammation, and neuronal apoptosis (Ji et al., 2021). Targeting the GS, therefore, has provided potential for the early risk assessment, diagnosis, prognosis, and therapeutic of stroke. In this review, we summarize the latest research progress in the GS, including the anatomy and function, the interaction with the meningeal lymphatic systems and the BBB, and the communication between astrocytes and other GS cellular components. We emphasize the role of the GS in pathophysiology of different stroke subtypes, especially the role of AQP4 in the pathophysiology of stroke. In the end, we summarize the concerns and give some perspectives for future research.

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