Microglia as the primary immune cells of brain act protective effects against injuries and infections in the central nervous system. Inflammation via excessive Ca(2+)influx and oxygen radical species (ROS) generation is a known factor in many neurodegenerative disorders. Importantly, the Ca(2+)permeable TRPM2 channel is activated by oxidative stress. Thus, TRPM2 could provide the excessive Ca(2+)influx in the microglia. Although TRPM2 expression level is high in inflammatory cells, the interplay between mouse microglia and TRPM2 channel during inflammation is not fully identified. Thus, it is important to understand the mechanisms and factors involved in order to enhance neuronal regeneration and repair. The data presented here indicate that TRPM2 channels were activated in microglia cells by interferon-gamma (IFN gamma). The IFN gamma treatment further increased apoptosis (early and late) and cytokine productions (TNF-alpha, IL-1 beta, and IL-6) which were due to increased lipid peroxidation and ROS generations as well as increased activations of caspase -3 (Casp-3) and - 9 (Casp-9). However, selenium treatment diminished activations of TRPM2, cytokine, Casp-3, and Casp-9, and levels of lipid peroxidation and mitochondrial ROS production in the microglia that were treated with IFN gamma. Moreover, addition of either PARP1 inhibitors (PJ34 or DPQ) or TRPM2 blockers (2-APB or ACA) potentiated the modulator effects of selenium. These results clearly suggest that IFN gamma leads to TRPM2 activation in microglia cells; whereas, selenium prevents IFN gamma-mediated TRPM2 activation and cytokine generation. Together the interplay between IFN gamma released from microglia cells is importance in brain inflammation and may affect oxidative cytotoxicity in the microglia.