Combined clemastine fumarate and selenomethionine promote remyelination via PI3K/Akt/mTOR signaling in experimental multiple sclerosis.

Multiple sclerosis is a chronic demyelinating disorder of the central nervous system characterized by neuroinflammation, oxidative stress, axonal injury, and progressive loss of myelin. Although currently available disease-modifying therapies effectively suppress immune activity, their ability to promote remyelination and neurological recovery remains limited. Clemastine fumarate (CMF), a first-generation antihistamine, has demonstrated remyelinating potential through the promotion of oligodendrocyte maturation, whereas selenomethionine (SLM), a selenium-containing antioxidant, may attenuate oxidative stress and inflammatory injury. As these agents target distinct yet complementary pathological mechanisms, their combined therapeutic potential in MS remains unexplored. Therefore, the present study investigated the neuroprotective and remyelinating effects of CMF and SLM, administered individually or in combination, in an ethidium bromide (EMBE)-induced demyelination model in adult Wistar rats (n = 8/group). Following ICP EMBE administration, animals received CMF (20 or 40 mg/kg, i.p.), SLM (5 mg/kg, i.p.), or combination treatment for 28 days. Behavioral, neurochemical, inflammatory, oxidative stress, apoptotic, and histopathological parameters were evaluated together with PI3K, Akt, and mTOR protein expression. EMBE administration produced marked motor and cognitive deficits, neurotransmitter imbalance, oxidative stress, neuroinflammation, apoptotic alterations, altered PI3K, Akt, and mTOR protein expression and extensive demyelination. Treatment with CMF and SLM significantly attenuated these pathological changes, with combination therapy producing the greatest overall benefit. Treatment was further associated with normalization of altered PI3K, Akt, and mTOR protein expression and substantial preservation of myelin integrity. CMF and SLM thus appear to exert complementary neuroprotective and remyelinating effects, CMF principally promoting oligodendrocyte-mediated remyelination and SLM limiting oxidative and inflammatory injury that together converge on the PI3K/Akt/mTOR axis, supporting simultaneous dual-target intervention as a rational strategy for MS.