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.

Keywords: blood-brain barrier; neurorehabilitation; peripheral and meningeal lymphatics.

Figure 1

Schematic illustration of three models of generation and pathways of interstitial fluid (ISF) in the brain. Model I explains the formation of ISF (10% of the total volume of ISF) as a result of metabolic oxidation of glucose to carbon dioxide and water; Model II explains the generation of ISF as a large fraction of cerebral capillary secretion of solutes, which are driven passively by the ionic gradient through the endothelial cell membranes (blue arrows) or via the tight junctions of (blood-brain barrier (BBB) and formed perivascular space (PVS—enlarged figure; arrows show movement of ISF) around penetrating arteries, venules, and veins, and connecting with glia-lines boundaries between neuropil and regions of axon tracts; Model III explains ISF as a fraction of recycled cerebral spinal fluid (CSF), which flows from the choroid plexus into the subarachnoid space and then into PVS where CSF is merged with ISF generated by cerebral capillaries.

Figure 2

A schematic illustration of connective bridge between the BBB opening (on the example of FITC-dextran) and activation of the lymphatic clearance: I illustrates the BBB opening for FITC-dextran (the red bolls); the green arrows show movement of the extravasated FITC-dextran from the brain tissues into the meningeal lymphatic vessels; II demonstrates movement of FITC-dextran in the cerebral lymphatic network; III show that after the BBB opening, FITC-dextran moves from the meningeal lymphatics (II) into the deep cervical lymph nodes (the red dotted boxes).