Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects

Sarah E. Fiedler, Vijayshree Yadav, Amelia R. Kerns, Catherine Tsang, Sheila Markwardt, Edward Kim, Rebecca Spain, Dennis Bourdette, Sonemany Salinthone

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Lipoic acid (LA) exhibits antioxidant and anti-inflammatory properties; supplementation reduces disease severity and T lymphocyte migration into the central nervous system in a murine model of multiple sclerosis (MS), and administration in secondary progressive MS (SPMS) subjects reduces brain atrophy compared to placebo. The mechanism of action (MOA) of LA’s efficacy in suppression of MS pathology is incompletely understood. LA stimulates production of the immunomodulator cyclic AMP (cAMP) in vitro. To determine whether cAMP could be involved in the MOA of LA in vivo, we performed a clinical trial to examine whether LA stimulates cAMP production in healthy control and MS subjects, and whether there are differences in the bioavailability of LA between groups. We administered 1200 mg of oral LA to healthy control, relapsing remitting MS (RRMS) and SPMS subjects, and measured plasma LA and cAMP levels in peripheral blood mononuclear cells (PBMCs). There were no significant differences between the groups in pharmacokinetic (PK) parameters. Healthy and SPMS subjects had increased cAMP at 2 and 4 h post-LA treatment compared to baseline, while RRMS subjects showed decreases in cAMP. Additionally, plasma concentrations of prostaglandin E2 (PGE2, a known cAMP stimulator) were significantly lower in female RRMS subjects compared to female HC and SPMS subjects 4 h after LA ingestion. These data indicate that cAMP could be part of the MOA of LA in SPMS, and that there is a divergent response to LA in RRMS subjects that may have implications in the efficacy of immunomodulatory drugs. This clinical trial, “Defining the Anti-inflammatory Role of Lipoic Acid in Multiple Sclerosis,” NCT00997438, is registered at https://clinicaltrials.gov/ct2/show/record/NCT00997438.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Nov 15 2017

Fingerprint

Chronic Progressive Multiple Sclerosis
Thioctic Acid
Cyclic AMP
Multiple Sclerosis
Dinoprostone
Anti-Inflammatory Agents
Clinical Trials
Relapsing-Remitting Multiple Sclerosis
Immunologic Factors
Biological Availability
Atrophy
Blood Cells

Keywords

  • Cyclic AMP
  • Lipoic acid
  • Multiple sclerosis
  • Pharmacokinetics
  • Prostaglandin E2
  • Thioctic acid

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects. / Fiedler, Sarah E.; Yadav, Vijayshree; Kerns, Amelia R.; Tsang, Catherine; Markwardt, Sheila; Kim, Edward; Spain, Rebecca; Bourdette, Dennis; Salinthone, Sonemany.

In: Molecular Neurobiology, 15.11.2017, p. 1-13.

Research output: Contribution to journalArticle

Fiedler, Sarah E. ; Yadav, Vijayshree ; Kerns, Amelia R. ; Tsang, Catherine ; Markwardt, Sheila ; Kim, Edward ; Spain, Rebecca ; Bourdette, Dennis ; Salinthone, Sonemany. / Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects. In: Molecular Neurobiology. 2017 ; pp. 1-13.
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abstract = "Lipoic acid (LA) exhibits antioxidant and anti-inflammatory properties; supplementation reduces disease severity and T lymphocyte migration into the central nervous system in a murine model of multiple sclerosis (MS), and administration in secondary progressive MS (SPMS) subjects reduces brain atrophy compared to placebo. The mechanism of action (MOA) of LA’s efficacy in suppression of MS pathology is incompletely understood. LA stimulates production of the immunomodulator cyclic AMP (cAMP) in vitro. To determine whether cAMP could be involved in the MOA of LA in vivo, we performed a clinical trial to examine whether LA stimulates cAMP production in healthy control and MS subjects, and whether there are differences in the bioavailability of LA between groups. We administered 1200 mg of oral LA to healthy control, relapsing remitting MS (RRMS) and SPMS subjects, and measured plasma LA and cAMP levels in peripheral blood mononuclear cells (PBMCs). There were no significant differences between the groups in pharmacokinetic (PK) parameters. Healthy and SPMS subjects had increased cAMP at 2 and 4 h post-LA treatment compared to baseline, while RRMS subjects showed decreases in cAMP. Additionally, plasma concentrations of prostaglandin E2 (PGE2, a known cAMP stimulator) were significantly lower in female RRMS subjects compared to female HC and SPMS subjects 4 h after LA ingestion. These data indicate that cAMP could be part of the MOA of LA in SPMS, and that there is a divergent response to LA in RRMS subjects that may have implications in the efficacy of immunomodulatory drugs. This clinical trial, “Defining the Anti-inflammatory Role of Lipoic Acid in Multiple Sclerosis,” NCT00997438, is registered at https://clinicaltrials.gov/ct2/show/record/NCT00997438.",
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