Excitotoxic programmed cell death involves caspase-independent mechanisms

Excitotoxicity is a common pathological process in many neurologic and neurodegenerative disorders, and this process involves over-stimulation of glutamate receptors and an excessive influx of calcium into cells. Cell death in excitotoxicity is unique in that, for the most part, it does not involve caspase-dependent pathways. Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) is an early pathological event in excitotoxicity that leads to a unique form of cell death called parthanatos. Biochemical events in parthanatos include early accumulation of poly (ADP-ribose) (PAR) and nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria followed by nuclear accumulation of macrophage migration inhibitory factor (MIF). MIF’s nuclease activity serves as the final executioner in excitotoxicity by shredding genomic DNA. Interfering with PARP activation, PAR signaling or MIF nuclease activity offers therapeutic interventions that could protect against a variety of neuronal injury due to a variety of insults involving glutamate excitotoxicity.