The long-term goal of this project is to determine the mechanisms by which the peroxisome proliferator-activated receptor (PPAR)-gamma modulates inflammatory diseases of the central nervous system (CNS), including multiple sclerosis (MS). The critical role of PPAR-gamma in glucose and lipid metabolism is well established. Recently, however, PPAR-gamma was also demonstrated to be a potent inhibitor of macrophage activation. Our studies indicated that PPAR-gamma ligands inhibited the activation of microglia in response to interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, cytokines that may contribute to the pathology associated with MS. In addition, PPAR-gamma is expressed by T cells and affects T-cell proliferation. PPAR-gamma ligands also indirectly affect T-cell function by inhibiting the production of T-cell active chemokines by endothelial cells. Importantly, PPAR-gamma ligands have recently been demonstrated to ameliorate a variety of inflammatory conditions, including arthritis, atherosclerosis, and inflammatory bowel disease. We have recently demonstrated that a PPAR-gamma ligand blocks the development of experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Collectively, these studies suggest that PPAR-gamma ligands may be efficacious in the treatment of MS. The mechanisms by which PPAR-gamma ligands modulate susceptibility to MS have not been elucidated. MS is believed to be initiated by autoreactive T cells. Activated microglia also contribute to MS development through production of a variety of molecules that may affect the viability of myelin-producing oligodendrocytes, and are capable of altering T-cell phenotype. The hypothesis of the proposed studies is that PPAR-gamma agonists (1) inhibit the activation of microglia resulting in protection of oligodendrocytes, (2) inhibit microglial production of chemokine and chemokine receptors believed to contribute to the movement of immune cells into the CNS in MS patients, (3) affect T-cell phenotype and apoptosis, and (4) inhibit the development of EAE. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arkansas for Medical Sciences
Anatomy/Cell Biology
Schools of Medicine
Little Rock
United States
Zip Code
Xu, Jihong; Racke, Michael K; Drew, Paul D (2007) Peroxisome proliferator-activated receptor-alpha agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis. J Neurochem 103:1801-10
Xu, Jihong; Drew, Paul D (2007) Peroxisome proliferator-activated receptor-gamma agonists suppress the production of IL-12 family cytokines by activated glia. J Immunol 178:1904-13
Zhang-Gandhi, Cindy X; Drew, Paul D (2007) Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes. J Neuroimmunol 183:50-9
Racke, Michael K; Gocke, Anne R; Muir, Mark et al. (2006) Nuclear receptors and autoimmune disease: the potential of PPAR agonists to treat multiple sclerosis. J Nutr 136:700-3
Xu, Jihong; Drew, Paul D (2006) 9-Cis-retinoic acid suppresses inflammatory responses of microglia and astrocytes. J Neuroimmunol 171:135-44
Drew, Paul D; Xu, Jihong; Storer, Paul D et al. (2006) Peroxisome proliferator-activated receptor agonist regulation of glial activation: relevance to CNS inflammatory disorders. Neurochem Int 49:183-9
Xu, Jihong; Chavis, Janet A; Racke, Michael K et al. (2006) Peroxisome proliferator-activated receptor-alpha and retinoid X receptor agonists inhibit inflammatory responses of astrocytes. J Neuroimmunol 176:95-105
Drew, Paul D; Storer, Paul D; Xu, Jihong et al. (2005) Hormone regulation of microglial cell activation: relevance to multiple sclerosis. Brain Res Brain Res Rev 48:322-7
Storer, Paul D; Xu, Jihong; Chavis, Janet A et al. (2005) Cyclopentenone prostaglandins PGA2 and 15-deoxy-delta12,14 PGJ2 suppress activation of murine microglia and astrocytes: implications for multiple sclerosis. J Neurosci Res 80:66-74
Storer, Paul D; Xu, Jihong; Chavis, Janet et al. (2005) Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol 161:113-22

Showing the most recent 10 out of 16 publications