The Role of Excitotoxic Programmed Necrosis in Acute Brain Injury

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Excitotoxicity involves the excessive release of glutamate from presynaptic nerve terminals and from reversal of astrocytic glutamate uptake, when there is excessive neuronal depolarization. N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptor, are activated in postsynaptic neurons, opening their receptor-operated cation channels to allow Ca2 +influx. The Ca2 +influx activates two enzymes, calpain I and neuronal nitric oxide synthase (nNOS). Calpain I activation produces mitochondrial release of cytochrome c (cyt c), truncated apoptosis-inducing factor (tAIF) and endonuclease G (endoG), the lysosomal release of cathepsins B and D and DNase II, and inactivation of the plasma membrane Na+-Ca2 +exchanger, which add to the buildup of intracellular Ca2 +. tAIF is involved in large-scale DNA cleavage and cyt c may be involved in chromatin condensation; endoG produces internucleosomal DNA cleavage. The nuclear actions of the other proteins have not been determined. nNOS forms nitric oxide (NO), which reacts with superoxide (O2-) to form peroxynitrite (ONOO-). These free radicals damage cellular membranes, intracellular proteins and DNA. DNA damage activates poly(ADP-ribose) polymerase-1 (PARP-1), which produces poly(ADP-ribose) (PAR) polymers that exit nuclei and translocate to mitochondrial membranes, also releasing AIF. Poly(ADP-ribose) glycohydrolase hydrolyzes PAR polymers into ADP-ribose molecules, which translocate to plasma membranes, activating melastatin-like transient receptor potential 2 (TRPM-2) channels, which open, allowing Ca2 +influx into neurons. NADPH oxidase (NOX1) transfers electrons across cellular membranes, producing O2-. The result of these processes is neuronal necrosis, which is a programmed cell death that is the basis of all acute neuronal injury in the adult brain.




Fujikawa, D. G. (2015). The Role of Excitotoxic Programmed Necrosis in Acute Brain Injury. Computational and Structural Biotechnology Journal. Elsevier.

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