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Mol Neurobiol. 2018 Jul;55(7):6037-6049. doi: 10.1007/s12035-017-0813-y. Epub 2017 Nov 15.

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

Author information

1
VA Portland Health Care System, Research and Development Service, Mail Code R&D8, 3710 SW US Veterans' Hospital Rd, Portland, OR, 97239, USA.
2
Department of Neurology, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
3
OCTRI Biostatistics and Design Program, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
4
VA Portland Health Care System, Research and Development Service, Mail Code R&D8, 3710 SW US Veterans' Hospital Rd, Portland, OR, 97239, USA. salintho@ohsu.edu.
5
Department of Neurology, Oregon Health and Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA. salintho@ohsu.edu.

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 .

KEYWORDS:

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

PMID:
29143287
PMCID:
PMC5953756
[Available on 2019-07-01]
DOI:
10.1007/s12035-017-0813-y
[Indexed for MEDLINE]

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