Blood–brain barrier: A novel therapeutic target in multiple sclerosis

Abstract

Multiple sclerosis is an autoimmune inflammatory disorder of the central nervous system, and the entrance of pathogenic lymphocytes from blood circulation into the brain across the blood–brain barrier (BBB) is accepted as the initial step of pathogenesis. The migration of lymphocytes across the BBB is mediated by their sequential interactions with the brain microvascular endothelial cells, the central component of the BBB, including rolling (loose attachment), adhesion (firm attachment), crawling and transmigration. There are a variety of cell adhesion molecules that are expressed on brain microvascular endothelial cells and are involved in this process. The selectins are assumed to be associated with the rolling of lymphocytes. Vascular cell adhesion molecule‐1 contributes to the adhesion of lymphocytes by binding to very late antigen‐4 on their surface after the stimulation by cytokines. Intercellular adhesion molecule‐1 acts for the adhesion as well and the subsequent crawling of lymphocytes by binding to leukocyte function‐associated antigen‐1 on their surface. Activated leukocyte cell adhesion molecule, melanoma cell adhesion molecule, platelet endothelial cell adhesion molecule‐1, nerve injury‐induced protein‐1 and vascular adhesion protein‐1 are also considered to influence the migratory process of lymphocytes across the BBB, although the detailed mechanisms are not elucidated. Here we review the pathophysiology of multiple sclerosis at the BBB to present a possible molecular targeted therapy in the future, especially focused on the molecules expressing at the brain microvascular endothelial cells.

Correlation Between Integrin Alpha-4 Gene Polymorphisms and Failure to Respond to Natalizumab Therapy in Iraqi Multiple Sclerosis Patients

“…The migration of lymphocytes across the BBB in MS is known to be significantly impacted by the binding of VLA-4 to VCAM-1 [37]. The current results revealed a significant decrease in VCAM-1 serum concentration in the responders as compared to the non-responders.…”

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

“…The contribution of the endothelial NMDA receptors [82], micro RNAs [83] and extracellular vesicles [84] are some of the more recent investigations in this regard. Restoration of these barriers have been a very promising strategy to control MS and other neurological pathologies [85,86]. As mast cells have been considered crucial regulators of this barrier permeability [87], the amount and activity of these cells was checked at the CNS.…”

Modulation of blood-brain barrier function by a heteroduplex oligonucleotide in vivo

“…BBB modulation may provide a potential platform for drug development to treat many intractable neurological disorders, because BMECs express various disease-specific pathological molecules 1 , 2 . In multiple sclerosis, for example, a variety of cell adhesion and signaling molecules are involved in lymphocyte migration from the blood into the brain across the BBB, which is the initial step of pathogenesis 20 , 21 . The most pivotal process in this step is the adhesion of very late antigen-4 (the synonym of α4β1-integrin) on lymphocytes to vascular cell adhesion molecule-1 (VCAM-1) on BMECs 22 .…”