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

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.

Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis

“…Several studies have provided evidence for vascular components participating in the complex pathogenetic network in multiple sclerosis (MS). Blood–brain barrier disruption and vascular changes, leading to cerebral hypoperfusion and tissue hypoxia, interact in a vicious cycle favoring the altered immune trafficking and the inflammatory events [ 1 , 2 , 3 ]. Most of the MS lesions have a perivascular development around small cerebral veins, a feature called “central vein sign” [ 4 , 5 ], which spreads across all MS clinical phenotypes.…”

Relationship between blood-brain permeability and antibodies against aquaporins in neuromyelitis optica spectrum disorders and multiple sclerosis patients

“…suppression of T-lymphocytes activation and proliferation, or reduction of proinflammatory cytokines' concentrations [48]. Furthermore, there is evidence for the stabilising effect of IFN-β on BBB [47]. We speculate that inflammation decrease due to treatment led to improvement of BBB properties Michalina Jasiak-Zatońska, Blood-brain permeability and antibodies against aquaporins in NMOsd and MS and reduction of serum levels of molecules, which could be markers of its breakdown.…”

“…In turn, BBB permeability increases in inflammation, as mentioned before. It is known that IFN-β and GA treatment moderate the inflammatory response [47]. IFN-β exerts various anti-inflammatory and immunomodulatory effects, e.g.…”

The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination

“…While we employed a reductionist approach to refine our understanding of how HMGB1 acts on primary OLs in culture, we recognize that there are other physiological activities attributed to how extracellular HMGB1 may impact the brain that were not examined in this study. For instance, HMGB1 has also been implicated in the breakdown of the BBB (Zhang et al, 2011 ; Nishibori et al, 2020 ), an integral component of MS pathophysiology (Balasa et al, 2021 ) and studies in MS patients corroborate this; serum levels of HMGB1 in MS patients are significantly higher than healthy controls (Bucova et al, 2020 ). Additionally, serum HMGB1 levels are also elevated in EAE.…”