Lipoic Acid Protects Efficiently Only against a Specific Form of Peroxynitrite-induced Damage

Abstract

The ability of the sulfur-containing compounds glutathione (GSH), glutathione disulphide (GSSG), S-methylglutathione (GSMe), lipoic acid (LA), and dihydrolipoic acid (DHLA) to protect against hypochlorous acid (HOCl)-mediated damage and peroxynitrite (ONOOH)-induced damage has been compared. Protective activity was assessed in competition assays by monitoring several detectors, i.e. dihydrorhodamine-123 (DHR-123) oxidation, ␣ 1 -antiproteinase (␣ 1 -AP) inactivation, and glutathione S-transferase P1-1 (GST-P1-1) inactivation. In addition, nitration of tyrosine was measured to assess protection of the sulfur-containing compounds against ONOOH. For protection against HOCl, the efficacy of the antioxidant was controlled by the ratio of the reaction rates of the antioxidant and the detector molecule with the oxidant. The rank order of the activity of the antioxidants (GSH > DHLA Ϸ LA Ϸ GSMe > GSSG) appeared to be independent of the detector used. However, the rank order of the antioxidants against ONOOH-induced damage is strongly dependent on the detector. LA was 40 times less active than GSH in the inhibition of ONOOH-induced DHR-123 oxidation, whereas LA was 20 times more active than GSH in preventing the inhibition of GST-P1-1 by ONOOH. This points to different molecular mechanisms of ONOOH damage to DHR-123 compared with ONOOH damage to GST-P1-1. LA is a poor antioxidant in protecting against the form of ONOOH damage involved in DHR-123 oxidation. In the form of ONOOH toxicity involved in GST-P1-1 inhibition, LA is the most potent sulfur-containing antioxidant in our series. It is proposed that an intermediate product in which both sulfur atoms of LA have reacted is involved in the reaction of ONOOH with LA. The high potency of LA to protect GST-P1-1 against ONOOH might be of therapeutic interest.

α-Lipoic Acid Inhibits Inflammatory Bone Resorption by Suppressing Prostaglandin E2 Synthesis

“…Lipid peroxides and peroxynitrite have both been implicated as the oxidants that oxidize ferric heme to a ferryl-oxo protoporphyrin radical (40). Previous reports have shown that LA can regenerate endogenous and exogenous antioxidants and scavenge free radicals, including lipid peroxides and peroxynitrite, in cells (13,41,42). Thus, this antioxidant property of LA may be involved in the inhibition of COX-2 and the subsequent decrease in PGE 2 synthesis.…”

2-Styrylchromones: Novel strong scavengers of reactive oxygen and nitrogen species

“…Hypochlorous acid scavenging assay. HOCl was measured by using a previously described fluorescent methodology, 54 based on the HOCl-induced oxidation of DHR to rhodamine 123, which has been adapted to a microplate reader. HOCl was prepared immediately before use by adjusting the pH of a 1% (m/v) solution of NaOCl to 6.2 with dropwise addition of 10% H 2 SO 4 .…”

Lipoic Acid in the Prevention of Acute Kidney Injury

“…The 2 sulfur atoms in the 1,2-dithiolane ring confers upon LA a high tendency for reduction of other redox-sensitive molecules. In contrast, the presence of 2 - SH groups in DHLA makes it more effective, on a molar basis, than glutathione (GSH) or N-acetylcysteine in protecting against α1-antiproteinse [8,9,10,11,12,13,14]. …”

“…The molecule α-LA (1,2-dithiolane-3-pentanoic acid) naturally exists in both prokaryotic and eukaryotic cells. Studies have shown that both α-LA and DHLA efficiently protect against cellular damage by peroxynitrite [9,12,13]. Moreover, peroxynitrite-derived carbonate and nitrogen dioxide radicals readily react with α-LA and DHLA [14].…”

“…Therefore, a strategy to inhibit ROS generation or scavenger free radicals becomes an important intervention to prevent CI-AKI [3]. Interestingly, a naturally occurring cellular antioxidant lipoic acid (LA) (1,2-dithilane-3-pentanoic acid) was reported to have potent antioxidant property, and it can serve as a free radical scavenger of ROS and reactive nitrogen oxide species (RNOS) [8,9,10,11,12,13,14]. …”