The role of scavenging antioxidants and the transcription factor NRF2 in protection against advanced glycation end products in a neuronal-derived cell line

Oxidative stress is implicated as a causal factor for diabetes-associated tissue complications. Cell and animal models of diabetes complications show an overall protective benefit of antioxidant treatments. Oxidative stress is achieved through several ROS-producing mechanisms in diabetes, so attention should be given to antioxidants that consistently show positive effects across several mechanisms of damage. In these studies, a cell culture model of diabetic neuropathy was used to test whether the lipid soluble antioxidant alpha-tocopherol or manipulation of intracellular GSH concentrations resulted in protection against AGEs. In our initial studies, alpha-tocopherol was relatively limited in its effects as it lowered lipid peroxidation and cell death but it had no effect on neurite degeneration and intracellular antioxidant status. Treatment with NAC had a pronounced effect by improving cell viability and maintaining neurite structure, which were observed with a concomitant increase in GSH. We next tested whether increasing GSH by chemically inducing activity of the transcription factor Nrf2 conferred benefit to cells exposed to AGEs. While the prototypical Nrf2-inducing antioxidant D3T protected against H2O 2, it surprisingly potentiated AGE-induced oxidative damage. The results demonstrated that effects of Nrf2 induction on oxidative damage depend heavily on the source of stress and mechanism of activation.