Therapeutic approaches to CNS diseases via the meningeal lymphatic and glymphatic system: prospects and challenges

Abstract

The brain has traditionally been considered an "immune-privileged" organ lacking a lymphatic system. However, recent studies have challenged this view by identifying the presence of the glymphatic system and meningeal lymphatic vessels (MLVs). These discoveries offer new opportunities for waste clearance and treatment of central nervous system (CNS) diseases. Various strategies have been developed based on these pathways, including modulation of glymphatic system function, enhancement of meningeal lymphatic drainage, and utilization of these routes for drug delivery. Consequently, this review explores the developmental features and physiological roles of the cerebral lymphatic system as well as its significance in various CNS disorders. Notably, strategies for ameliorating CNS diseases have been discussed with a focus on enhancing glymphatic system and MLVs functionality through modulation of physiological factors along with implementing pharmacological and physical treatments. Additionally, emphasis is placed on the potential use of the CNS lymphatic system in drug delivery while envisioning future directions in terms of mechanisms, applications, and translational research.

Keywords: CNS diseases; drug delivery; glymphatic system; meningeal lymphatic vessels; neurodegenerative diseases.

FIGURE 1

The scheme of therapeutic approaches to CNS diseases via the meningeal lymphatic and glymphatic systems. Created with Biorender.com. Abbreviations: CSF, cerebrospinal fluid; ISF, interstitial fluid; MLVs, meningeal lymphatic vessels; dcLNs, deep cervical lymph nodes; AQP4, Aquaporin-4; DBS, deep brain stimulation; rTMS, repetitive Transcranial Magnetic Stimulation.

FIGURE 2

Under traditional CSF drainage patterns (left), the CSF, producing in the ventricular arachnoid mater, circulates within the subarachnoid space before ultimately being reabsorbed back into the blood circulation. In the emerging CSF drainage model under the participation of the glymphatic system (right), the CSF can access the brain parenchyma via perivascular spaces surrounding the arteries, subsequently exchange with the ISF, which infiltrates into the subarachnoid space containing CSF via perivascular spaces surrounding the veins (reproduced from Lohela et al., 2022, with permission from Springer Nature). Abbreviations: CSF, cerebrospinal fluid; ISF, interstitial fluid.

FIGURE 3

Schematic illustration of the CNS venous and lymphatic systems in mice and humans (A) A summary of the mouse head’s lymphatic CSF draining circuitry. (B) Diagram showing the human dural venolymphatic complex with lymphatic discharges (reproduced from Jacob et al., 2022, licensed under CC BY 4.0). Abbreviations: RE, respiratory epithelium; OE, olfactory epithelium; NP, nasopharynx; mLN, mandibular lymph node; amLN, accessory mandibular LN; IOS, inferior olfactory sinus; SOS, superior olfactory sinus; RCS, rostral confluence of sinuses; CAV, cavernous sinus; SSS, superior sagittal sinus; PSS, petrosquamous sinus; SS, sigmoid sinus; IPETS, inferior petrosal sinus; dcLN, deep cervical LN; sfc, foramen caecum; pef, posterior ethmoid foramen; cpf, cribriform plate foramina; alf, anterior lacerated foramen; cc, carotid canal; ipf, interpterygoid foramen; ica, internal carotid artery; pfv, posterior facial vein; psf, petrosquamous fissure; jf, jugular foramen; ijv, internal jugular vein; SPS, superior petrosal sinus; StS, straight sinus; TS, transverse sinus; SS, sigmoid sinuses; MS, marginal sinus; cLNs, cervical LNs; sof, superior orbital fissure; fr, foramen rotundum; fo, foramen ovale.