Molecular Mechanisms and Therapeutic Potential of Natural Neuroprotective Compounds in Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System characterized by immune-mediated demyelination, axonal damage, and progressive neurodegeneration, which critically contributes to irreversible disability. Currently, disease-modifying therapies are effective in treating inflammatory relapses, but only partially in preventing long-term neurodegeneration and disability progression, making the identification of effective neuroprotective strategies a clinical priority. In this context, natural molecules have attracted growing interest, and they have emerged as promising candidates for neuroprotection due to their multiple biological activities and safety profiles. Growing evidence suggests that major classes of bioactive molecules, including polyphenols, antioxidant compounds, and terpenoids, have neuroprotective effects through the regulation of redox homeostasis, mitochondrial function, and immune responses. These compounds act through pathways such as nuclear factor erythroid 2-related factor 2-mediated antioxidant signaling, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cell-driven neuroinflammation, and modulation of T cells, supporting neuronal survival and oligodendrocyte function. In preclinical models of demyelination, these compounds have been associated with a reduction in clinical severity, decreased inflammatory peripheral infiltration, and increased cellular resilience. Although clinical data remain heterogeneous, these natural products have shown potential benefits in inflammatory markers and functional outcomes. This review synthesizes mechanistic and translational insights to highlight the therapeutic potential and current limitations of natural neuroprotective agents in MS, with the aim of guiding future research toward clinically effective actions.