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.
Presently there are over 6,000 veterans who are service connected for multiple sclerosis (MS) and a total of 14,000 Veterans with MS receive care through VHA in any one year. Currently, the VA spends $274 million dollars treating veterans with MS. These treatments are only partially effective, expensive or require daily, weekly or monthly subcutaneous injections or intravenous administration. Developing new therapies that can be used independently or in conjunction with current disease modifying therapies is therefore relevant to the mission of the VA. To this end, lipoic acid (LA) may be a promising alternative. It is orally active in humans, highly effective as a therapeutic agent in the animal model of MS, and is considerably less expensive than current disease modifying therapies. Better understanding of the effects of LA on immune cell function and the signaling pathways that mediate these effects will allow us to use LA as an independent treatment for MS or as a complement/adjunct treatment strategy to current therapies, which can potentially improve their efficacy.
|Fiedler, Sarah E; Yadav, Vijayshree; Kerns, Amelia R et al. (2018) Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects. Mol Neurobiol 55:6037-6049|
|Fiedler, Sarah E; Kerns, Amelia R; Tsang, Catherine et al. (2017) Donor variability may mask dimethyl fumarate's effects on nuclear factor E2-related factor 2 in human peripheral blood mononuclear cells. BMC Res Notes 10:553|
|Fiedler, Sarah E; George, Joshua D; Love, Haley N et al. (2017) Analysis of IL-6, IL-1? and TNF-? production in monocytes isolated from multiple sclerosis patients treated with disease modifying drugs. J Syst Integr Neurosci 3:|