CMX-2043 Mechanisms of Action In Vitro. Issue 3 (September 2016)

• Record Type: Journal Article
• Authors: Lader, Alan S.; Baguisi, Alexander; Casale, Ralph; Kates, Steven A.; Beeuwkes, Reinier
• Is Part Of: Journal of cardiovascular pharmacology. Volume 68:Issue 3(2016)
• Publication Date: 2016-09
• Subjects: ischemia-reperfusion injury -- cytoprotection -- Akt activation -- CMX-2043 -- lipoic acid; Cardiovascular Diseases -- drug therapy -- Periodicals; Cardiovascular System -- drug effects -- Periodicals; Cardiovascular pharmacology -- Periodicals; Cardiovascular agents -- Periodicals; Cardiovascular agents; Cardiovascular pharmacology; Periodicals; 615.7105
• DOI: 10.1097/FJC.0000000000000408
• Languages: English
• ISSNs: 0160-2446

Abstract

Abstract : Abstract: α-Lipoic acid has been shown to provide cytoprotection in some tissues through antioxidant and antiapoptotic mechanisms. We have enhanced these properties by synthetic modification, resulting in a new chemical entity, CMX-2043, with proven efficacy in an animal model of cardiac ischemia-reperfusion injury. The present studies compare cytoprotective cellular pathways of R-α-lipoic acid and CMX-2043. Biochemical and cellular assays were used to compare antioxidant potency, tyrosine kinase activation, and protein kinase B (Akt) phosphorylation. CMX-2043 was more effective than lipoic acid in antioxidant effect, activation of insulin receptor kinase, soluble tyrosine kinase, and Akt phosphorylation. Activation of insulin-like growth factor 1 receptor was similar for both. CMX-2043 stimulation of Akt phosphorylation was abolished by the phosphatidylinositide 3-kinase inhibitor LY294002. Consistent with Akt activation, CMX-2043 reduced carbachol-induced calcium overload. The S-stereoisomer of CMX-2043 was less active in the biochemical assays than the R-isomer. These results are consistent with cytoprotection through activation of Akt and antioxidant action. CMX-2043 may thus provide a pharmacological approach to cytoprotection consistent with established anti-apoptotic mechanisms.