Bridging Inflammation and Neurodegeneration in Multiple Sclerosis: Mechanisms and Emerging Therapies

Multiple sclerosis (MS) is characterized by a complex interplay between inflammation and neurodegeneration that evolves over time. Although current immunotherapies effectively reduce relapses in relapsing-remitting MS, they fail to prevent long-term progression, particularly in progressive subtypes of MS. This review explores the mechanisms linking inflammation to axonal loss, with an emphasis on mitochondrial dysfunction, oxidative stress, and microglial activity. It also critically evaluates the limitations of existing disease-modifying therapies in addressing progression independent of relapse activity. Emerging central nervous system-penetrant strategies, including Bruton's tyrosine kinase inhibitors, remyelinating agents, and neuroprotective compounds, are discussed as promising approaches to target compartmentalized pathology. Emphasis is placed on the need for integrated therapeutic approaches that target both inflammatory and degenerative disease processes. Finally, this review highlights the key knowledge gaps, advances in biomarker development, and future research directions that could guide the development of the next generation of MS therapies.