Prolonged seizures and cellular injury: understanding the connection.
Status epilepticus (SE)-induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic N-methyl-D-aspartate (NMDA) receptors and triggers receptor-mediated calcium influx (excitotoxicity). This results in activation of intracellular proteases and neuronal nitric oxide synthase, with generation of free radicals, and damage to cellular membranes, structural proteins, and essential enzymes. Programmed cell death mechanisms, such as p53 activation, activation of cell death-promoting Bcl-2 family members, and endonuclease-induced DNA laddering, occur in SE-induced neuronal death. Caspase-independent excitotoxic mechanisms, such as NMDA-induced calpain I activation, with activation and translocation of the cell death-promoting Bcl-2 family member Bid from cytoplasm to mitochondria, and subsequent translocation of apoptosis-inducing factor and endonuclease G to nuclei (which cause large-scale and internucleosomal DNA cleavage, respectively), may be triggered by SE. Poly(ADP-ribose) polymerase-1 (PARP-1) activation and cysteinyl cathepsin and DNase II release from lysosomes may occur following SE as well, but these events await future investigation. In the future, rational combinations of central nervous system-penetrable neuroprotective agents, based on our knowledge of excitotoxic mechanisms, may be useful in refractory human SE.
Fujikawa
Denson G
DG
Experimental Neurology Laboratory, VA Greater Los Angeles Healthcare System, Sepulveda, CA, USA. dfujikaw@ucla.edu
D000818:Animals; D016923:Cell Death / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009414:Nerve Growth Factors / Q000502:physiology; D009474:Neurons / Q000166:cytology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000503:physiopathology*; D013226:Status Epilepticus / Q000503:physiopathology*
D009414:Nerve Growth Factors; D016194:Receptors, N-Methyl-D-Aspartate