The antioxidant 3H-1,2-dithiole-3-thione potentiates advanced glycation end-product-induced oxidative stress in SH-SY5Y cells.
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.
Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA. robert.pazdro@jax.org
Robert
R
Pazdro
John R
JR
Burgess
D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D000975:Antioxidants; D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D005978:Glutathione; C049325:1,2-dithiol-3-thione