Acting centrally or peripherally: A renewed interest in the central nervous system penetration of disease-modifying drugs in multiple sclerosis

Abstract

With the recent approval of cladribine tablets, siponimod and ozanimod, there has been a renewed interest into the extent to which these current generation disease-modifying therapies (DMTs) are able to cross into the central nervous system (CNS), and how this penetration of the blood-brain barrier (BBB) may influence their ability to treat multiple sclerosis (MS).The integrity of the CNS is maintained by the BBB, blood-cerebrospinal fluid barrier, and the arachnoid barrier, which all play an important role in preserving the immunological environment and homeostasis within the CNS. The integrity of the BBB decreases during the course of MS, with a putative temporal relationship to disease worsening. Furthermore, it is currently considered that progression of the disease is mediated mainly by resident cells of the CNS.The existing literature provides evidence to show that some of the current generation DMTs for MS are able to penetrate the CNS and potentially exert direct effects on CNS-resident cells, in particular the CNS-penetrating prodrugs cladribine and fingolimod, and other sphingosine-1 phosphate receptor modulators; siponimod and ozanimod. Other current generation DMTs appear to be restricted to the periphery due to their high molecular weight or physicochemical properties.As more effective brain penetrant therapies are developed for the treatment of MS, there is a need to understand whether the potential for direct effects within the CNS are of significance, and whether this brings additional benefits over and above treatment effects mediated in the periphery. In turn, this will require an improved understanding of the structure and function of the BBB, the role it plays in MS and subsequent treatments.This narrative review summarizes the data supporting the biological plausibility of a potential benefit from therapeutic molecules entering the CNS, and discusses the potential significance in the current and future treatment of MS.

The Dual Role of the β2-Adrenoreceptor in the Modulation of IL-17 and IFN-γ Production by T Cells in Multiple Sclerosis

“…Almost all pathogenetic MS treatments affect Th17 cell function [ 8 ]. The effect of these treatments on immune cells in the CNS still needs to be clarified, suggesting the relevance of the new therapeutic approaches that allow the modulation of the Th17 immune response directly in the CNS [ 9 ]. In this regard, the effect of catecholamines on Th17 cells has attracted increasing attention.…”

Th17-cells in depression: Implication in multiple sclerosis

“…It is important to note, that antidepressants can affect inflammation directly in the CNS, while the ability of monoclonal antibodies to migrate through blood-brain barrier is limited, which suggests their effect primarily on the periphery ( 66 ). In this regard, the potential ability of antidepressants to modulate Th17-mediated neuroinflammation in MS has drawn a great attention.…”

Cladribine Tablets for Relapsing–Remitting Multiple Sclerosis: A Clinician’s Review

“…Studies have indicated that cladribine has the potential to penetrate the CNS and achieve a concentration in the cerebrospinal fluid of up to 25% of its concentration in plasma [ 28 – 30 ], which raises the possibility that cladribine tablets may be able to reduce lymphocyte numbers within the CNS as well as those circulating in the periphery [ 31 , 32 ]. However, a need exists to better understand if the potential for direct effects of cladribine within the CNS are clinically significant in terms of additional benefits over and above treatment effects on peripheral immune cells [ 33 ].…”