Activation of Caspase-Independent Programmed Pathways in Seizure-Induced Neuronal Necrosis

  • Denson G. FujikawaEmail author


Prolonged epileptic seizures, or status epilepticus (SE), produce morphologically necrotic neurons in many brain regions. In contrast to prior notions of cellular necrosis being a passive process of cell swelling and lysis, SE-induced necrotic neurons show internucleosomal DNA cleavage (DNA laddering), a programmed process requiring endonuclease activation. The underlying mechanisms are triggered by excessive activation of NMDA receptors by glutamate, which allows calcium influx through their receptor-operated cation channels (excitotoxicity). Calcium-dependent enzymes are activated, such as calpain I and neuronal nitric oxide synthase (nNOS), the latter of which, through production of reactive oxygen species (ROS), activates poly(ADP-ribose) polymerase-1 (PARP-1). Calpain I and PARP-1 activation in turn cause translocation of death-promoting mitochondrial proteins and lysosomal enzymes that degrade cytoplasmic proteins and nuclear chromatin, creating irreversible cellular damage. Another programmed necrotic cell death pathway, necroptosis, has been described in cell culture following caspase inhibition, and activation of this pathway has been described following cerebral ischemia and traumatic brain injury in vivo. However, whether this pathway interacts with the excitotoxic pathway, while likely, and the specific mechanisms by which this occurs, are at present unknown. Based upon our knowledge of excitotoxic mechanisms, neuroprotective strategies can be devised that could ameliorate neuronal necrosis from refractory SE in humans.


Calpain I Excitotoxicity Glutamate Necroptosis Neuronal nitric oxide synthase (nNOS) Poly(ADP-ribose) polymerase-1 (PARP-1) Programmed pathways Status epilepticus 


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyVA Greater Los Angeles Healthcare SystemNorth HillsUSA
  2. 2.Department of Neurology and Brain Research Institute, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA

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