Leukotriene inhibitors in multiple sclerosis: a systematic review of animal studies

Current disease-modifying therapies for multiple sclerosis (MS) primarily target adaptive immunity but often fail to halt neurodegeneration or promote myelin repair. Leukotriene pathway inhibitors, established in the management of asthma, possess anti-inflammatory and potentially neuroprotective properties. Following the PRISMA 2020 recommendations, a systematic search was conducted in PubMed, Web of Science, and Scopus. Eligible studies included preclinical investigations of leukotriene inhibitors in MS animal models and risk of bias was assessed using SYRCLE's risk of bias tool for animal studies. Five studies met the inclusion criteria, reported that inhibition of leukotriene B4 (LTB4) or cysteinyl leukotriene receptor 1 (CysLT1) attenuated clinical severity in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination models. Mechanistically, the included preclinical studies suggest that leukotriene inhibitors may influence several pathways potentially relevant to MS pathophysiology, including T helper 17 (Th17) cell differentiation, M1-like microglial polarization, and oligodendrocyte precursor cell (OPC) differentiation. In addition, targeted central nervous system (CNS) delivery using engineered exosomes appeared to enhance the observed remyelination effects. Leukotriene inhibition may exert pleiotropic effects across both peripheral immune responses and the CNS microenvironment. Although these mechanistic observations provide biological plausibility for further investigation of these agents as potential repurposed therapies for MS, particularly in the context of remyelination and neuroinflammation, they remain based on preclinical evidence and should therefore be considered hypothesis-generating. Well-designed clinical studies are required to determine whether these experimental effects translate into clinically meaningful therapeutic benefits in patients with MS.