Actions of disease-modifying multiple sclerosis (MS) drugs at the blood-brain barrier (BBB). Drug names were searched for in PubMed with the keywords ‘blood brain barrier’, ‘endothelial’, ‘endothelium’, ‘astrocyte’, ‘pericyte’ and ‘tight junction’. Results were reviewed and the most relevant associations are discussed. All references for this table are included in the online supplementary table 2
| Drug | Drug action | Effects at the BBB |
| IFN-β-1a and IFN-β-1b | Cytokines that modulate immune function | Reduces BBB permeability through actions on TJs and reduces expression of adhesion molecules for immune cell egress. |
| Glatiramer acetate | Pool of peptides antigenically similar to MBP with an immunomodulatory role | Specifically enhances Th2 lymphocyte migration across the BBB. Enhances activated dendritic cells migration across the BBB, possibly through RhoA activation. Enhances production of brain-derived neurotrophic factor (BDNF) which decreases blood-spinal cord barrier permeability—another related neurotrophic factor, GDNF, reduces BBB permeability. |
| Mitoxantrone | Immunosuppressive agent targeting DNA of immune cells | Globally cytotoxic, so likely does influence BBB but specific studies are sparse. Shown to influence PPAR-α in ECs in a BBB model. Also has effects on microglia that could affect the BBB. |
| Dimethyl fumarate | Immunomodulatory agent, possibly through activation of Nrf2 pathway | Reduces cerebral oedema in a mouse stroke model. Promotes BBB integrity through actions on TJs and decreased MMP activity through Nrf2 and casein kinase 2 signalling |
| Natalizumab | Monoclonal antibody targeting alpha-4 integrin, affecting immune cell adherence to endothelium | Blockade of alpha-4 integrin (aka VLA-4) on lymphocytes and monocytes directly affects egress of cells through the BBB, and decreases the number of Gd-enhancing lesions on MRI. One MRI showed that there was no difference between natalizumab and placebo in levels of subtle BBB leakage in non-Gd-enhancing lesions, but a recent in vitro study has shown that natalizumab partially inhibits the BBB disruptive effect of soluble VCAM-1 on alpha-4 integrin expressed on ECs. |
| Fingolimod | Sphingosine 1-phosphate receptor inhibitor, affects lymphocyte egress from lymph nodes | In a study incubating sera from patients with MS with brain microvascular ECs, fingolimod prevented BBB disruption by upregulating the TJ protein claudin-5 and downregulating the adhesion molecule VCAM-1. Similar roles in preserving BBB integrity have been shown in EAE models. However, another study showed that fingolimod did not enhance BBB integrity in inflammatory conditions and in fact was associated with decreased expression of occludin. Others say fingolimod reduces EC death in the presence of inflammatory cytokines. Astrocyte production of ceramides, which disrupt BBB function, is inhibited by fingolimod in MS. In particular, there are striking increases in ceramide production in astrocytic end-feet, suggesting a direct link with the BBB. Importantly, S1P1 modulation on astrocytes is required for fingolimod efficacy in EAE. |
| Teriflunomide | Dihydroorotate dehydrogenase inhibitor, affecting pyrimidine synthesis in immune cells | No known direct link |
| Alemtuzumab | Monoclonal antibody targeting CD52, causing depletion of monocytes and lymphocytes | One review suggests a potential link to ‘recovery of BBB integrity’ since anti-CD52 therapy restored intestinal epithelial function in a mouse model of inflammatory bowel disease; otherwise no direct link known. |
| Daclizumab | Monoclonal antibody targeting CD25, a component of the IL2 receptor, reducing T-cell responses | No direct link known—one paper suggests that since a reduction in contrast enhancing lesions in MRI takes~2 months to occur, then daclizumab does not have a BBB effect but works through immunomodulation. |
| Ocrelizumab | Monoclonal antibody targeting CD20 that depletes B cells | No known direct link |
| Laquinimod | Immunomodulatory agent, acting through the quinolone-3-carboxamide pathway | Decreases T-cell migration into the CNS in an EAE model through an effect on the endothelium. In vitro treatment reduces expression of ICAM-1 and ALCAM on endothelium, increases expression of adherent junction protein p120 and TJ protein ZO-1, and increases transendothelial electrical resistance indicating a direct effect on BBB integrity. Also decreases Th1 and Th17 lymphocyte transmigration and downregulates the astrocytic response. One poster abstract suggests that laquinimod reduces MMP-7, MMP-10 and VEGF-A expression (all of which are implicated in BBB disruption) in response to IL-1b treatment in vivo. |
CNS, central nervous system; EC, endothelial cell; Gd, gadolinium; GDNF,glial cell line-Derived Neurotrophic Factor MMP, matrix metalloproteinase; PPAR, Peroxisome Proliferator-Activated ReceptorTJ, tight junction;VCAM,Vascular Cell Adhesion Molecule, VLA,Very Late Antigen.