Nitric oxide plays a dual role in the oxidative injury of cultured rat microglia but not astroglia

Nitric oxide (NO) and oxidative stress caused by reactive oxygen species (ROS) accumulation are two important factors that lead to the progression of human neurological diseases. NO can be detrimental or protective to neurons under oxidative toxicity; however, in the case of brain exposure to oxidative stress, in addition to neurons, the existence of glia may also be disturbed by toxic ROS. The influence NO will have on ROS-mediated glial injury remains unclear. Here, we examined the effects of NO on cell viability under oxidative stress induced by hydrogen peroxide (H2O2) in rat primary mixed glia cultures, as well as pure astroglia and microglia cultures. We found that in mixed glia cultures, both H2O2 and NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) elicited cell death in a concentration-dependent manner. Combinations of H2O2 and SNAP at sublytic concentrations were sufficient to damage mixed glia, and sublytic concentrations of SNAP could reduce the insults that resulted from toxic H2O2. Furthermore, in microglia or astroglia, sublytic concentrations of H2O2 were toxic when combined with SNAP, and the potency was increased with an increased SNAP concentration. In microglia but not astroglia, a toxic H2O2-induced apoptotic injury was attenuated by a sublytic level of SNAP. H2O2 at toxic levels activated p38 mitogen-activated protein kinases (MAPK) and p53 pathways and increased DNA double strand breaks (DSBs) in microglia, whereas the rescue exerted by sublytic SNAP against toxic H2O2 occurred via the activation of both Akt and extracellular-signal-regulated kinase (ERK) cascades and decreased DNA DSBs. Moreover, a sublytic concentration of SNAP induced both heat shock protein 70 and heme oxygenase-1, which may be involved in decreasing the susceptibility of microglia to H2O2 toxicity. These results suggest that NO exhibits a concentration-dependent dual action of weakening or enhancing oxidative injury in mixed glia, particularly microglia.

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