Kasheke, Gracious2025-06-262025-06-262025-06-24https://hdl.handle.net/10222/85171Current immune-based therapies for multiple sclerosis (MS) reduce disease relapses but have limited value in slowing disease progression. Remyelination in the central nervous system (CNS) is considered essential for functional recovery in MS. This has driven an intense search for drugs that promote myelin repair. This thesis compared the efficacy of four putative remyelinating drugs at promoting motor recovery in a mouse model of MS termed experimental autoimmune encephalomyelitis (EAE). EAE recapitulates many pathophysiological features of MS including autoimmune mediated demyelination and axonal damage. Furthermore, we have shown that EAE produces MS-like gait deficits in mice. Kinematic gait analysis was therefore employed to identify drugs that promote functional recovery in EAE mice. To this end, we compared the effects of oral administration of pioglitazone, VP3.15, olesoxime, or IRX4204 beginning at peak disease on EAE-induced gait deficits. Unlike pioglitazone, VP3.15, and olesoxime, IRX4204 reduced clinical scores, loss of knee average angle, and elevation of knee and ankle RMS differences. These gait improvements in IRX4204-treated EAE mice were associated with transcriptional and histological signs of reduced inflammation, increased remyelination, and enhanced axonal integrity in the spinal cord. Experimentation with a mouse microglial cell line and primary astrocyte cultures showed that IRX4204 suppressed the expression of pro-inflammatory cytokines induced by treatment with lipopolysaccharide. IRX4204 also enhanced mitochondrial function and the phagocytotic activity of microglia. These findings support the potential of IRX4204 to increase functional recovery in MS by stimulating myelin repair. However, IRX4204 suffers from poor CNS uptake and adverse side effects caused by actions on cells outside of the CNS. To overcome these problems, we developed an intranasal nanoparticle formulation of IRX4204 designed to preferentially deliver this drug to the CNS. Our findings suggest that intranasal nanoparticle delivery is a promising strategy to improve the safety and efficacy of IRX4204 but also reveal limitations of this approach.enIRX4204Retinoid X receptorMultiple sclerosisRemyelinationKinematic gait analysisExperimental autoimmune encephalomyelitis