Multiple sclerosis is a chronic immune-mediated neurodegenerative disorder characterized by inflammation, demyelination, axonal injury, and progressive neurological disability. Although current disease-modifying therapies effectively reduce relapse frequency and peripheral immune activation, they provide limited protection against long-term neurodegeneration and remyelination failure. Emerging evidence suggests that neurotransmitter receptor-linked intracellular signaling pathways play crucial roles in regulating neuroinflammation, glial function, and neuronal survival. This review comprehensively examines the interconnected roles of the CHRM1, H1R, and the PI3K/Akt/mTOR signaling pathway in MS pathophysiology. CHRM1 and H1R both G protein-coupled receptors widely expressed in neurons, glial cells, and immune cells, modulate intracellular calcium signaling, cytokine production, blood-brain barrier integrity, and oligodendrocyte precursor cell dynamics. Dysregulated activation of these receptors contributes to persistent neuroinflammation, impaired remyelination, and synaptic dysfunction. Downstream, the PI3K/Akt/mTOR axis functions as a critical integrative hub controlling cell survival, metabolism, autophagy, and myelin protein synthesis. Balanced activation of this pathway promotes neuronal protection and oligodendrocyte maturation, whereas its chronic dysregulation exacerbates mitochondrial dysfunction, oxidative stress, and axonal degeneration. By synthesizing current experimental and mechanistic evidence, this review highlights the functional cross-talk between cholinergic and histaminergic signaling and their convergence on PI3K/Akt/mTOR-mediated cellular responses. Understanding these interconnected molecular networks provides a foundation for developing multi-target therapeutic strategies aimed at simultaneously reducing neuroinflammation, enhancing neuroprotection, and promoting remyelination in progressive MS.
