Elucidating the mechanisms that mediate the effects of lipoic acid in MS

Portland Va Medical Center, Portland OR

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Abstract

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an often disabling disease of the central nervous system (CNS) that affects more than 2.5 million people worldwide. Current FDA approved disease modifying therapies for MS such as beta interferon are only partially effective, are costly and have side effects. Thus, there is a need for the continued development of new treatment strategies and targets for successful management of MS. The antioxidant lipoic acid (LA) has been shown to reduce disease severity and T lymphocyte migration into the spinal cord in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We have shown that LA stimulates cyclic AMP (cAMP) production in immune cells. cAMP is a small molecule second messenger that has immunosuppressive function. Additionally, LA inhibits proinflammatory cytokine production and T cell activation. However, the effects of LA on other immune cell types implicated in the pathogenesis of MS, such as macrophages, and the mechanisms of action of LA are not fully understood. We hypothesize that the mechanisms of action of LA involves 1) activation of cAMP/AKAP/PKA signaling cascade, 2) suppression of activation and function of Th1 and Th17 T cells while promoting regulatory T cell (Treg) activation, expansion and function; and 3) suppression of monocyte/macrophage function. To accomplish the goals of this grant, the following objectives are planned: (1) Determine if Protein Kinase A (PKA) and A-Kinase Anchoring Proteins (AKAPs) mediate LA suppression of T cell activation and function. (2) Determine if LA suppresses the pathogenic phenotype in human T cell subpopulations (i.e. by promoting Treg expansion and function while inhibiting Th1/Th17 proliferation and function). (3) Determine the effects of LA on peripheral monocyte/macrophage production of proinflammatory mediators, migration and phagocytosis. A better understanding of the mechanisms that mediate the effects of LA will provide knowledge and insights for pursuing and maximizing the use of LA as a new treatment strategy for MS. Mechanistic understanding of the cAMP-mediated action of LA will provide guidance in issues relating to drug delivery, dosage requirement, and potentially even in the diagnosis or treatment of different forms or stages of MS.