Reviewing the Significance of Blood-Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment.

Rodica Balasa,Doina Manu,Laura Barcutean,Oana Mosora

doi:10.3390/ijms22168370

Abstract

The disruption of blood–brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained ‘inside-out’ demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB’s endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.

Highlights

Multiple sclerosis (MS) remains the most frequent cause of nontraumatic disabling disease in young adults [1]
Several studies have demonstrated the complex role of the blood–brain barrier (BBB) in immune surveillance of the central nervous system (CNS), the immune preservation of the brain being subjected to the integrity of the BBB
We present its mechanism of action, it has not yet been approved for MS treatment, as it diffuses freely across the BBB and does not need active transport due to its small dimension that allows for passive crossing

Summary

Introduction

Multiple sclerosis (MS) remains the most frequent cause of nontraumatic disabling disease in young adults [1]. Drastic morphological changes of the lymphocytes allow tethering and rolling at the level of the junctional proteins, leading to the onset of transendothelial selectin-mediated migration This multi-step process is orchestrated by numerous molecules, such as vascular cell adhesion molecules (VCAM), intracellular adhesion molecules (ICAM), cytokines and inflammatory mediators, together with endothelial alteration of transcellular and paracellular transport (Figure 1) [19,20]. Depending on the patient, the progression of brain atrophy is related less to BBB breakdown and more to self-sustaining in the central compartment It is transient, and recurrence may be observed in different locations, but may occur in the same spot (evident on MRI as lesions with a ring enhancement or with a blurred rim) [36].

Metabolic Changes in BBB Cells

Microvasculature

BBB in Progressive Forms of MS

Chronic MS DMTs with Central Effect beyond the BBB

Findings

Conclusions