The Role of Excitotoxic Programmed Necrosis in Acute Brain Injury

Publication date: Available online 28 March 2015 Source:Computational and Structural Biotechnology Journal Author(s): Denson G. Fujikawa 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 adds 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 A...
Source: Computational and Structural Biotechnology Journal - Category: Biotechnology Source Type: research