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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Acknowledgements
The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Dennis Koop at the OHSU Bioanalytical Shared Resource/Pharmacokinetics Core for measuring the plasma LA concentrations. We also thank OCTRI, which provided clinical coordination, nursing services, and blood processing.
Funding
This work was supported by a Clinical Science Research and Development Service Career Development Award and a Biomedical Laboratory Research and Development Service Merit Review (1I01BX001793), both from the US Department of Veterans Affairs. The statistical analyses in this publication were supported by The Portland VA Research foundation and by the Oregon Clinical and Translational Institute (OCTRI), National Institutes of Health (NIH), grant UL1TR000128 from the National Center for Advancing Translational Sciences (NCATS).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Fiedler, S.E., Yadav, V., Kerns, A.R. et al. Lipoic Acid Stimulates cAMP Production in Healthy Control and Secondary Progressive MS Subjects. Mol Neurobiol 55, 6037–6049 (2018). https://doi.org/10.1007/s12035-017-0813-y
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DOI: https://doi.org/10.1007/s12035-017-0813-y