FIGURE 2.

The cellular death pathway of oxidative glutamate toxicity. Excessive accumulation of glutamate in the extracellular environment inhibits cystine uptake through System Xc^–, resulting in GSH deficiency in cells. Mitochondrial complex I increases about 6 h after glutamate exposure. At the same time, 12/15-LOX is activated and 12/15-hydroxyhexotetraenoic acid is produced, and 12/15-LOX directly damages mitochondria and increases production of ROS. Additionally, soluble functional acid cyclase is activated, and intracellular GMP content is increased. Subsequently, cGMP opens calcium channels and enables calcium influx. After glutamate exposure for about 10–12 h, ROS and intracellular calcium levels reach their peaks, and AIF is transferred from mitochondria to the nucleus, inducing nuclear coagulation and cellular death.