Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis

It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor alpha (PPAR alpha), here, we established that oral administration of gemfibrozil preserved the integrity of blood-brain barrier (BBB) and blood-spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPAR alpha-/- mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPAR beta (formerly PPAR delta), indicating an important role of PPAR beta/delta, but not PPAR alpha, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPAR alpha-/- EAE mice, but not PPAR beta-/- EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPAR alpha, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPAR beta, but not PPAR alpha.