Blood–Brain Barrier, Lymphatic Clearance, and Recovery: Ariadne’s Thread in Labyrinths of Hypotheses

Abstract

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria, and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the cerebral lymphatic functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in brain drainage, clearance, and recovery is still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on the connective bridge between the opening of a blood–brain barrier and activation of the meningeal lymphatic clearance. The ability to stimulate the lymph flow in the brain, is likely to play an important role in developing future innovative strategies in neurorehabilitation therapy.

Spinal cerebrospinal fluid flow is increased in rats with elevated intracranial pressure 18 hours after cortical ischaemic stroke

“…Several CSF drainage hypotheses have been presented in recent years and we are yet to meet a consensus on the topic [24][25][26]. In recent years, lymphatic drainage of CSF from both the cranium and the spinal space have gained merit in the eld, with several groups demonstrating the presence of CSF tracers in the peripheral lymphatic system, primarily the cervical lymphatics [21,[27][28][29][30].…”

Biophotonic Strategies of Measurement and Stimulation of the Cranial and the Extracranial Lymphatic Drainage Function

“…The fact that LVs, rather than the veins, are the major outflow pathway for both large and small molecular tracers in mice was demonstrated by Ma et al [195]. Panel (b) of the figure displays the mechanism of "pulsationassisted diffusion" , which many critics of the glymphatic hypothesis suggest as the more likely mechanism [17], [177], [178], [196]. According to this mechanism, the rapid transport of substances in any direction is possible due to the fact that ar-terial pulsations create oscillations of fluid, which dramatically accelerates diffusion even at zero net flow.…”

“…The mechanism to major extent relies on the fact that arterial pulsations create a directed bulk flow of CSF from the pial membrane (1) to the parenchyma region near PVS (2). However, this pumping is a weak point of the hypothesis and has caused the main criticism of the hypothesis as a whole, as we mentioned above [17], [178], [193], [194]. Also, this mechanism makes impossible the fast release substances from the opened blood-brain barrier (BBB) (3), and especially the erythrocytes to the meningues, since they cannot move freely through the parenchyma, and in the periarterial space they would have to move upstream.…”

“…T HE lymphatic door from and into the brain is Yin and Yang in the cerebral homeostasis. Over the last few decades, the crucial role of the cerebral lymphatics in keeping the central nervous system (CNS) health has been actively debated [1]- [17]. The lymphatic mechanisms of removal of metabolites and toxins from the brain tissues orchestrate recovery processes in the CNS [17].…”

“…Over the last few decades, the crucial role of the cerebral lymphatics in keeping the central nervous system (CNS) health has been actively debated [1]- [17]. The lymphatic mechanisms of removal of metabolites and toxins from the brain tissues orchestrate recovery processes in the CNS [17]. The lymphatic abnormalities are accompanied by suppression of the cerebral spinal fluid (CSF) outflow that contributes the elevation of intracranial pressure (ICP) [18].…”