Calpain inhibition reduces oligodendroglial death and mitochondrial alterations in response to excitotoxicity. Cells were treated with AMPA and kainate (KA) receptor agonists for 15 min, in the absence or presence of calpain inhibitors PD150606 (100 μm), calpeptin (20 μm), or MDL 28170 (10 μm). A, Cell viability was determined by a calcein-AM assay after 24 h. All calpain inhibitors used significantly reduced oligodendrocyte death caused by AMPA or kainate exposure. B, C, ROS production and mitochondrial potential were monitored by measuring DCFDA (20 μm) and JC-1 (3 μm) fluorescence, respectively. The presence of PD150606 inhibited AMPA and kainate receptor-mediated ROS generation and mitochondrial depolarization. *p < 0.05, **p < 0.01, ***p < 0.001, compared with cells treated with agonist alone.