Hindawi Publishing Corporation Experimental Diabetes Research Volume 2012, Article ID 137607, 8 pages doi:10.1155/2012/137607 Research Article The Antioxidant 3H-1,2-Dithiole-3-Thione Potentiates Advanced Glycation End-Product-Induced Oxidative Stress in SH-SY5Y Cells Robert Pazdro 1, 2 and John R. Burgess 1 1 Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA 2 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA Correspondence should be addressed to Robert Pazdro, robert.pazdro@jax.org Received 6 September 2011; Revised 24 February 2012; Accepted 26 February 2012 Academic Editor: N. Cameron Copyright © 2012 R. Pazdro and J. R. Burgess. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Oxidative stress is implicated as a major factor in the development of diabetes complications and is caused in part by advanced glycation end products (AGEs). AGEs ligate to the receptor for AGEs (RAGE), promoting protein kinase C (PKC)- dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and superoxide radical generation. While scavenging antioxidants are protective against AGEs, it is unknown if induction of endogenous antioxidant defenses has the same effect. In this study, we confirmed that the compound 3H-1,2-dithiole-3-thione (D3T) increases reduced-state glutathione (GSH) concentrations and NADPH:quinone oxidoreductase 1 (NQO1) activity in SH-SY5Y cells and provides protection against H 2 O 2 . Surprisingly, D3T potentiated oxidative damage caused by AGEs. In comparison to vehicle controls, D3T caused greater AGE-induced cytotoxicity and depletion of intracellular GSH levels while offering no protection against neurite degeneration or protein carbonylation. D3T potentiated AGE-induced reactive oxygen species (ROS) formation, an effect abrogated by inhibitors of PKC and NADPH oxidase. This study suggests that chemical induction of endogenous antioxidant defenses requires further examination in models of diabetes. 1. Introduction Oxidative stress is a primary component of diabetes pathol- ogy [1] and is considered a causal factor for the development of complications like neuropathy [2], which is characterized by hyperalgesia and sensory dysfunction [3–5]. Antioxidants suppress oxidative stress and ameliorate symptoms of dia- betic neuropathy in experimental systems [6, 7], and while antioxidants have the potential to provide clinical benefit [8], more studies are required to properly investigate the effectiveness of antioxidants in humans. Concentrations of reactive oxygen species (ROS) are ele- vated in diabetes due to increased mitochondrial superoxide radical generation and depletion of endogenous antioxidant systems [9–11]. ROS are also the result of advanced gly- cation end products (AGEs), which are produced by the nonenzymatic glycation of proteins [12, 13]. Carboxymethyl lysine (CML)—a regularly formed product of protein glycation [14]—ligates to the receptor for AGEs (RAGE) [15], facilitating activation of extracellular signal-regulated kinase (ERK) [16], p38 kinase [17], and the transcription factor NF-kappaB [17]. In neuronal cells, RAGE ligation increases protein kinase C (PKC)-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and superoxide radical generation [18, 19]. This pathway of ROS generation causes apoptosis and macromolecule damage in vitro [19, 20] as well as functional neurological deficits in vivo [21–23]. Antioxidants such as probucol [23], α-tocopherol [24], α-lipoic acid [25], and N-acetyl-cysteine (NAC) [23, 25, 26] provide cytoprotection against AGEs. NAC exerts its protective effects by increasing intracellular GSH [27, 28]; studying alternative methods of increasing intracellular GSH might highlight additional mechanisms that protect neurons