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UBC Theses and Dissertations

Metabolic treatments in murine models of multiple sclerosis Alaeiilkhchi, Nima


Multiple sclerosis (MS) is a debilitating neurological disorder characterized by autoimmune-driven demyelination within the central nervous system (CNS). Impaired remyelination contributes to the progressive stage of MS, ultimately leading to axonal and neuronal degeneration, exacerbating disability. Currently, no remyelination treatments exist for MS, and therapeutic options for progressive MS are limited. Furthermore, the impact of metabolism and dietary interventions on MS prevention and treatment remains unclear. Recent evidence suggests that ketogenic diet (KD) may offer potential benefits for individuals with MS, though its restrictive nature poses compliance challenges. To facilitate the development of targeted pharmacological treatments, this dissertation investigates the mechanisms underpinning KD benefits in preclinical murine models of MS, hypothesizing that ketone body production mediates these effects. In Chapter 2, I administered KD and intraperitoneal ketone esters (iKE) in a murine cuprizone/rapamycin (Cup/R) demyelination model, and observed enhanced myelin debris clearance, oligodendrocyte lineage cell differentiation, and remyelination. In Chapter 3, I utilized the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS and administered dietary ketone esters (KED) and found that KED conferred prophylactic and therapeutic benefits comparable to KD. Mechanisms behind KED's efficacy were explored, showing that KED can promote proliferation, recruitment, and differentiation of oligodendrocyte lineage cells by targeting the hydroxycarboxylic acid receptor 2 (HCAR2). In Chapter 4, I combined KED with metformin to synergistically augment KED's benefits, observing a significantly enhanced prophylactic effect in the KED + Metformin combination. Overall, this dissertation demonstrates that ketone esters can effectively substitute KD in providing benefits in murine models of MS. Moreover, combining ketone esters with metformin results in a synergistic accumulation of benefits, offering potential avenues for future MS treatment strategies.

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