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 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). A small pilot trial of LA therapy showed reduced brain atrophy in MS patients compared to placebo. However, the mechanisms of action of LA are not fully understood, thus limiting advancement of this agent to large multi-site trials. 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 pro-inflammatory cytokine production and T cell activation. LA also exhibits anti-oxidant properties by activation of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) signaling cascade in response to oxidative stress. The goal of this grant is to determine the biochemical mechanisms by which LA may treat and/or halt progression of MS with the hope that we can translate our in vitro results to the in vivo setting. We hypothesize that LA has protective effects in MS and that these effects may be mediated in part by the cAMP and/or Nrf2 signaling cascades. To accomplish the goals of this grant, the following objectives are planned: (1) Determine the effects of LA on human cells implicated in the pathogenesis of MS and the mechanisms that mediate these responses; (2) Determine if LA treatment enhances blood brain barrier (BBB) integrity and the mechanisms that mediate these responses; and (3) Determine the in vivo effects of LA in a specialized EAE model that develops cortical lesions. A better understanding of the mechanisms of action 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 LA will provide guidance in issues relating to toxicities, contraindications, and potentially in the diagnosis or treatment of different forms or stages of MS.