Neuroprotective strategies in multiple sclerosis: a status update and emerging paradigms

MS is a disease continuum in which maladaptive inflammation and neurodegeneration co-occur from onset and evolve over time. Recent progress in the understating of MS pathobiology creates new perspectives for novel neuroprotective therapeutic strategies. The authors briefly review the mechanisms underlying inflammation and neurodegeneration in MS and discuss the current and emerging strategies to promote neuroprotection in MS. Data were derived in large part from extensive review of the published literature available on PubMed (up to 5th of March 2025). Strategies for neuroprotection should be ideally implemented early in the course of MS. They should consider the interplay between neuroinflammation, demyelination and neurodegeneration, the maladaptive changes in the CNS innate immunity resident cells, axonal mitochondrial dysfunction (axonal response of mitochondria to demyelination, ARMD), and remyelination. There is a need for adequate biomarkers that can help to monitor outcomes of target engagement. Comorbidities and aging can worsen neurodegeneration and impair neuroprotective/regenerative processes. Candidate drugs from preclinical and early clinical studies should be tested in multi-arm multistage adaptive trials.