# Mechanisms of action: the effects of lipoic acid on macrophages,endothelial cells and CNS function in MS

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9815417
- **Project number:** 5I01BX001793-07
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Sonemany Salinthone
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-01-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815417

## Citation

> US National Institutes of Health, RePORTER application 9815417, Mechanisms of action: the effects of lipoic acid on macrophages,endothelial cells and CNS function in MS (5I01BX001793-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815417. Licensed CC0.

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