Unlocking dexmedetomidine's therapeutic potential in multiple sclerosis: Dual modulation of PI3K/Akt/BDNF and...

Multiple sclerosis (MS) is an enduring autoimmune and neurodegenerative disease affecting the central nervous system with inflammation, demyelination, and axonal degeneration that progresses to neurological impairment. Despite available treatments, their limited efficacy, inability to promote remyelination, and associated adverse reactions highlight the need for unconventional therapies. This study investigated the therapeutic potential of dexmedetomidine (DEX), a selective α2-adrenergic receptor (α2AR) agonist, in a rat model of MS triggered by experimental autoimmune encephalomyelitis (EAE). EAE was induced in male Sprague Dawley rats using guinea pig spinal cord homogenate and complete Freund's adjuvant, replicating MS-like pathology. DEX (10 μg/kg/day, i.p.) was administered for 14 days, significantly improved motor function and muscle coordination, as shown by enhanced performance in the open field, rotarod, and hanging wire tests, along with reduced pain sensitivity in the Randall-Selitto test. Histological analyses (H&E and TEM) confirmed increased axonal remyelination and paralleling improvements in clinical scores. Mechanistically, DEX activated α2AR, stimulating the PI3K/p-Akt pathway and promoting CREB phosphorylation. This cascade upregulated BDNF and TrkB gene expression and enhanced neuronal remyelination and survival. Additionally, DEX exhibited potent anti-inflammatory effects by suppressing HMGB1, thereby downregulating TLR4 expression and inhibiting the pS536-NF-κB p65/TNF-α axis. This shift was evidenced by reduced CD86 immunoreactivity and increased CD163 expression, indicating a transition toward an anti-inflammatory phenotype. In conclusion, DEX exerts neuroprotective effects in EAE-induced MS by simultaneously triggering the PI3K/Akt/CREB/BDNF/TrkB pathway and hindering the HMGB1/TLR4/NF-κB/TNF-α cascade, leading to reduced neuroinflammation and enhanced remyelination. Therefore, DEX represents a promising MS treatment, warranting further clinical exploration.