Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms

Abstract

Lipoic acid (LA) is a naturally occurring fatty acid that exhibits anti-oxidant and antiinflammatory properties and is being pursued as a therapeutic for many diseases including multiple sclerosis, diabetic polyneuropathy and Alzheimer's disease. We previously reported on the novel finding that racemic LA (50:50 mixture of R and S LA) stimulates cAMP production, activates prostanoid EP2 and EP4 receptors and adenylyl cyclases (AC), and suppresses activation and cytotoxicity in NK cells. In this study we present evidence that furthers our understanding of the mechanisms of action of LA. Using various LA derivatives, dihydrolipoic acid (DHLA), S,Sdimethyl lipoic acid (DMLA) and lipoamide (LPM), we discovered that only LA is capable of stimulating cAMP production in NK cells. Furthermore, there is no difference in cAMP production after stimulation with either R-LA, S-LA or racemic LA. Competition and synergistic studies indicate that LA may also activate AC independent of the EP2 and EP4 receptors. Pretreatment of PBMCc with KH7 (a specific peptide inhibitor of soluble AC) and the calcium inhibitor (Bapta) prior to LA treatment resulted in reduced cAMP levels, suggesting that soluble AC and calcium signaling mediate LA stimulation of cAMP production. In addition, pharmacological inhibitor studies demonstrate that LA also activates other G-protein coupled receptors, including histamine and adenosine, but not the beta adrenergic receptors. These novel findings provide information to better understand the mechanisms of action of LA, which can help facilitate the use of LA as a therapeutic for various diseases.

Alpha-lipoic acid-loaded nanostructured lipid carrier: sustained release and biocompatibility to HaCaT cellsin vitro

“…Endogenous ALA works as a covalently bound dithiol cofactor for essential mitochondrial enzymes and other multienzyme complexes, comprising those of branched-chain a-keto acid dehydrogenase enzyme complexes, such as pyruvate dehydrogenase, a-ketoglutarate dehydrogenase and glycine decarboxylase, and is negatively charged compared to the neutral charge of lipoamide (Rackham et al, 2011;Houng et al, 2012). As an antioxidant, ALA and its reduced form, dihydrolipoic acid (DHLA), have been considered as owning reactive oxygen species scavenging action (Salinthone et al, 2011;Al Rasheed et al, 2012). It is an extraordinary radical scavenger in both the oxidized and reduced form, and is recognized to revitalize other antioxidants from their inactive forms (Kennedy & Wan, 2011).…”

“…It is an extraordinary radical scavenger in both the oxidized and reduced form, and is recognized to revitalize other antioxidants from their inactive forms (Kennedy & Wan, 2011). ALA also works as a chelator of transition and heavy metals (Salinthone et al, 2011) and can assist regenerate endogenous antioxidants for example glutathione, ascorbic acid, vitamin E and metal-chelating activity (Salinthone et al, 2011;Al Rasheed et al, 2012).…”

“…Exogenous resources of ALA are acquired by the intake of foodstuff and supplement (Salinthone et al, 2011). ALA has been displayed to be advantageous in improving diverse disease state (Lu et al, 2011a).…”

“…ALA has been displayed to be advantageous in improving diverse disease state (Lu et al, 2011a). Commercially accessible ALA complements are being employed as unconventional and/or complementary beneficials for diseases for example vitamin C and E deficiency, Alzheimer's disease, degenerative processes in neurons, diabetic polyneuropathy, ischemia/ reperfusion injuries, joint diseases, atherosclerosis and AIDS (Lu et al, 2011a,b;Salinthone et al, 2011). ALA has been proved to possess anti-inflammatory properties and medicinal advantages which may be correlated with its antioxidant characteristic in more recent times (Salinthone et al, 2011).…”

“…Commercially accessible ALA complements are being employed as unconventional and/or complementary beneficials for diseases for example vitamin C and E deficiency, Alzheimer's disease, degenerative processes in neurons, diabetic polyneuropathy, ischemia/ reperfusion injuries, joint diseases, atherosclerosis and AIDS (Lu et al, 2011a,b;Salinthone et al, 2011). ALA has been proved to possess anti-inflammatory properties and medicinal advantages which may be correlated with its antioxidant characteristic in more recent times (Salinthone et al, 2011). In addition, it is not only confined to its antioxidant properties and even dopaquinone trapping, but also enlarged to hinder the expression of microphthalmia-associated transcription factor (MITF, a regulator of melanocyte development and survival), and accordingly impeding tyrosinase expression and action as well as promoting skin lightening (Lu et al, 2011a).…”