Multiple sclerosis (MS) is an enduring, immune-mediated condition of the central nervous system (CNS) and a major reason for neurological impairment in young people (Attia et al., 2023; Oh et al., 2018). It is distinguished by neuroinflammation, myelin degradation, and axonal damage, leading to brain and spinal cord atrophy (Lassmann, 2018). MS results in a heterogeneous array of symptoms including, motor, cognitive, sensory and visual dysfunctions, based on the damaged area of the CNS (Adamec and Habek, 2013; Garg and Smith, 2015). Current therapies are costly, have side effects, and fail to promote remyelination, emphasizing the need for more effective, affordable treatments with anti-neuroinflammatory properties (Bierhansl et al., 2022; Piehl, 2021).

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for exploring MS (Procaccini et al., 2015), due to its strong resemblance to the disease's immunopathology in MS patients and its utility in testing novel therapeutics (Constantinescu et al., 2011). EAE is produced through the administration of myelin antigens, such as spinal cord homogenate (SCH), which is effective, simple, and cost-efficient (Burrows et al., 2019). This leads to intense immune activation, triggering inflammatory cascades, which contribute to neuroinflammation, neuronal damage, and demyelination. (Kwilasz et al., 2021b; Liu et al., 2019).

The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway plays a pivotal role in MS pathogenesis by mediating neuroinflammation and myelin dysfunction (Mc Guire et al., 2013; Zheng et al., 2020). TLR4, expressed in CNS cells like microglia (Wei et al., 2023), is activated by high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) released from damaged cells (Leitner et al., 2019). This activation triggers NF-κB, amplifying inflammation and promoting demyelination and axonal damage (Chu et al., 2021; Paudel et al., 2019). Given its role in disease progression, the suppression of TLR4/NF-κB hub is being explored as a therapeutic strategy to mitigate neuroinflammation and prevent further neurodegeneration in MS and other neurodegenerative diseases (Oh et al., 2024; Paudel et al., 2019).

In parallel, phosphatidylinositol 3-kinase (PI3K)/protein kinase-B (Akt) cassette demonstrates a crucial function in modulating the TLR4/NF-κB signaling cascade, thereby reducing neuroinflammation and neuronal apoptosis (Cianciulli et al., 2020; Zhao et al., 2014). Its activation suppresses NF-κB nucleation and microglial activation, promoting neuronal survival and remyelination (Zhu et al., 2018). By regulating downstream executers such as the cAMP response element-binding protein (CREB), this pathway enhances neuroprotection and remyelination against neurological disorders (Meffre et al., 2015). CREB, in turn, upregulates brain-derived neurotrophic factor (BDNF), which supports neurogenesis, synaptic plasticity, and neuronal survival by activating tropomyosin receptor kinase B (TrkB). This interaction establishes a positive feedback loop that further strengthens neuroprotective mechanisms within the CNS (Zarneshan et al., 2022).

The very selective α2-adrenergic receptor (α2AR) agonist, dexmedetomidine (DEX), has shown a significant therapeutic potential in modulating PI3K/Akt and TLR4/NF-κB signaling cascades (Zhao et al., 2020). While primarily used as an anesthetic for its sedative, anxiolytic, and analgesic effects (Gertler et al., 2001), DEX also exerts neuroprotective properties by lowering neuroinflammation, apoptosis, and oxidative stress (Akpinar et al., 2016; Wang et al., 2022; Xie et al., 2021). Recent studies demonstrated its role in improving sevoflurane-induced cognitive deficits through TLR4/NF-κB inhibition (Wei et al., 2021) and mitigating EAE by desensitizing CXCR7 in microglia (Huang et al., 2018), further highlight its relevance in neurodegenerative disorders.

Accordingly, the present work aimed to explore the possible neuroprotective effects of DEX in an EAE rat model, with a focus on its role in modulating key inflammatory and neurodegenerative pathways. Specifically, the study highlighted DEX's ability to regulate the TLR4/NF-κB/HMGB1/TNF-α trajectory, which drives neuroinflammation and demyelination, as well as its influence on the PI3K/Akt/CREB/BDNF/TrkB pathway, which is central for neuronal survival and repair.