Lipoic Acid Attenuates Inflammation via cAMP and Protein Kinase A Signaling

Abstract

BackgroundAbnormal regulation of the inflammatory response is an important component of diseases such as diabetes, Alzheimer's disease and multiple sclerosis (MS). Lipoic acid (LA) has been shown to have antioxidant and anti-inflammatory properties and is being pursued as a therapy for these diseases. We first reported that LA stimulates cAMP production via activation of G-protein coupled receptors and adenylyl cyclases. LA also suppressed NK cell activation and cytotoxicity. In this study we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are mediated by the cAMP/PKA signaling cascade. Additionally, we show that LA oral administration elevates cAMP levels in MS subjects.Methodology/Principal FindingsWe determined the effects of LA on IL-6, IL-17 and IL-10 secretion using ELISAs. Treatment with 50 µg/ml and 100 µg/ml LA significantly reduced IL-6 levels by 19 and 34%, respectively, in T cell enriched PBMCs. IL-17 levels were also reduced by 35 and 50%, respectively. Though not significant, LA appeared to have a biphasic effect on IL-10 production. Thymidine incorporation studies showed LA inhibited T cell proliferation by 90%. T-cell activation was reduced by 50% as measured by IL-2 secretion. Western blot analysis showed that LA treatment increased phosphorylation of Lck, a downstream effector of protein kinase A. Pretreatment with a peptide inhibitor of PKA, PKI, blocked LA inhibition of IL-2 and IFN gamma production, indicating that PKA mediates these responses. Oral administration of 1200 mg LA to MS subjects resulted in increased cAMP levels in PBMCs four hours after ingestion. Average cAMP levels in 20 subjects were 43% higher than baseline.Conclusions/SignificanceOral administration of LA in vivo resulted in significant increases in cAMP concentration. The anti-inflammatory effects of LA are mediated in part by the cAMP/PKA signaling cascade. These novel findings enhance our understanding of the mechanisms of action of LA.

Does Lipoic Acid Consumption Affect the Cytokine Profile in Multiple Sclerosis Patients: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial

“…However, a 5-year investigation among MS patients did not reveal the influence of IL-4 in the process of this disease [22]. In spite of our results and taking into account the role of LA on IL-6, recent studies have suggested that LA, playing an anti-inflammatory role and activating protein kinase A and increasing the cAMP, can reduce the IL-6 level in MS patients [28]. LA may indirectly affect IL-4 via the other cytokines.…”

“…Multiple sclerosis (MS) is a chronic disabling autoimmune and demyelination disease of the central nervous system (CNS) [1,2]. High levels of proinflammatory factors, the increasing production of free radicals and oxidative stress in CNS are related to the pathogenesis of this disease [3].…”

Over-the-counter anti-oxidant therapies for use in multiple sclerosis: A systematic review

“…61 Of the 12 studies included in this review, one reported findings in both humans and animals 62 and four examined the effects of ALA supplements in people with MS or their blood products from two samples of patients. [62][63][64][65] The remaining preclinical studies utilized the EAE rodent model. 42,62,[66][67][68][69][70][71] Detailed information is found in Supplementary Table 5 and risk-of-bias assessments in Supplementary Figure 4(a) and (b).…”

Studies on Mechanistic Role of Natural Bioactive Compounds in the Management of Obesity An Overview

“…Distinct combinations and dietary influence can induce the anti-inflammatory effects of these fatty acids on the body. Alpha-lipoic acid T cells 50 and 100 µg/ml 5 min ↓ IL-6 levels, ↓ IL-17 ,↓ inflammation via cAMP and protein kinase A signaling [111] ↓, decrease; ↑, increase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; IL, interleukin; LA; alpha-lipoic acid; Sp1, SV40 promoter-1; cAMP, cyclic adenosine monophosphate.…”

“…These alterations improve mitochondrial function by stimulating organelle biogenesis, increasing fatty acid oxidation and reducing inflammation [109][110][111].…”