Targeting the α7-nicotinic acetylcholine receptor in multiple sclerosis: Implications for immunomodulation and neuroprotection.

Multiple sclerosis (MS) is a chronic immune-mediated disorder characterized by demyelination, axonal degeneration, and progressive neurological disability. Current disease-modifying therapies (DMTs) inadequately address neurodegeneration and remyelination failure, particularly in progressive MS. The α7-nicotinic acetylcholine receptor (α7-nAChR), a key mediator of the cholinergic anti-inflammatory pathway, has emerged as a promising therapeutic target that bridges immunomodulation and neuroprotection. This review synthesizes current evidence on the biology, distribution, and signaling of α7-nAChR in the context of MS pathogenesis. Activation of α7-nAChR suppresses NF-κB and MAPK signaling while stimulating JAK2/STAT3 pathways, reducing pro-inflammatory cytokine production and promoting regulatory immune responses. In the central nervous system (CNS), α7-nAChR activation has been reported to exert these effects in experimental models or may support oligodendrocyte resilience and remyelination. Preclinical studies in experimental autoimmune encephalomyelitis and toxin-induced demyelination models demonstrate that α7-nAChR activation alleviates inflammation, demyelination, and axonal damage. However, clinical translation faces challenges, including receptor desensitization, limited CNS penetration, and the absence of validated biomarkers. Emerging strategies, biased agonism, positive allosteric modulation, and rational combination therapies, offer promising avenues to overcome these obstacles. By integrating immunomodulatory and neuroprotective actions, α7-nAChR targeting represents a mechanistically compelling strategy for comprehensive disease modification in MS, although clinical translation remains contingent upon overcoming significant pharmacological and biomarker-related challenges. Nevertheless, its pleiotropic actions warrant further investigation in well-designed clinical trials, with potential implications for other neurodegenerative disorders.