Abstract
Diabetes mellitus is one of the most common chronic diseases and peripheral neuropathy (PN) affects at least 50% of diabetic patients. Medications available for patients ameliorate symptoms (pain) but do not protect against cellular damage, and come with severe side effects leading to discontinued use. In our lab we use differentiated SH‐SY5Y cells treated with advanced glycation end products (AGE) as a model to mimic diabetic conditions and to study the mechanisms of oxidative stress (OS) mediated cell damage and antioxidant protection. Nacetylcysteine (NAC), a common supplement, was previously shown in our lab to fully protect against AGE‐induced damage. Here we report that NAC confers protection by maintaining intracellular glutathione (GSH), suggesting that GSH plays a critical role in neurite protection. Our lab has also shown that 3H‐1,2‐dithiole‐3‐thione (D3T), a cruciferous vegetable constituent and potent inducer of nuclear factor (erythroid‐derived 2)‐ like (Nrf2), can significantly increase cellular GSH concentrations and protect against H2O2–induced cell death. Paradoxically, D3T conferred no protection against AGE‐induced cell death or neurite degeneration. Furthermore, D3T increased reactive oxygen species (ROS) generation, depleted GSH, and increased glucose‐6‐phosphate dehydrogenase (G6PD) expression, suggesting its role as an NADPH generating agent may promote OS rather than provide protection. Inhibition of NADPH generation via G6PD, the protein product of a Nrf2‐responsive gene, with dehydroepiandrosterone was found to protect against AGE‐induced ROS generation, loss of viability, and neurite degeneration. These results suggest that using a strategy to protect against oxidative stress by upregulation of the endogenous antioxidant defense system via Nrf2 may backfire and promote further damage if the products of upregulation contribute to ROS generation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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