Multiple sclerosis (MS) is an autoimmune disease that results in the expansion of pathogenic T cells specific for myelin autoantigens [45]. The disease manifests in the destruction of myelin sheaths and the inflammatory activation of glial cells [46]. Experimental autoimmune encephalomyelitis (EAE), in which mice are immunized with the encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide, is used as a model of MS [47, 48]. The potential role of PPARδ in demyelinating diseases was first proposed in a model that attempted to explain the detrimental effects of inflammatory mediators on myelin synthesis. Specifically, tumor necrosis factor alpha (TNF-α), a cytokine implicated in demyelinating pathologies, was demonstrated to attenuate PPARδ expression in OPCs and, concurrently, decrease very long-chain fatty acid (VLCFA) β-oxidation. The hypothetical model proposed that decreased PPARδ expression would lead to VLCFA accumulation, which would induce cytotoxic effects and demyelination. PPARδ agonists, therefore, were postulated to be beneficial for MS-affected individuals [49].
