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Caspase-2 activation is redundant during seizure-induced neuronal death

D C Henshall1, S L Skradski, D P Bonislawski

  • 1Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA. dehnsall@DowNeurobiology.org

Journal of Neurochemistry
|May 2, 2001
PubMed

Insights

Seizure-induced neuronal death involves caspase-2 activation in the hippocampus. However, blocking caspase-2 activity did not prevent DNA fragmentation or neuron death, suggesting alternative cell death pathways.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Neuronal death following seizures is a significant concern in epilepsy.
  • The caspase family of proteases plays a role in programmed cell death.
  • Caspase-2's specific involvement in seizure-induced neuronal death requires further investigation.

Purpose of the Study:

  • To investigate the role of caspase-2 in a rat model of kainic acid-induced limbic seizures.
  • To determine if caspase-2 activation correlates with neuronal injury and cell death markers.
  • To assess the impact of inhibiting caspase-2 on seizure-induced neuronal death.

Main Methods:

  • Induction of focal limbic seizures using kainic acid microinjection in rats.
  • Continuous electroencephalogram (EEG) monitoring for seizure activity.
  • Measurement of caspase-2 activity and expression, including cleaved caspase-2 and associated proteins (RAIDD, RIP, TRADD).
  • Assessment of Val-Asp-Val-Ala-Asp (VDVADase) activity as a marker for caspase-2 activation.
  • Pharmacological inhibition of caspase-2 using z-VDVAD-fluoromethyl ketone.
  • Evaluation of DNA fragmentation and neuronal death.

Main Results:

  • Caspase-2 was detected in both cytoplasmic and nuclear compartments of neurons.
  • Cleaved caspase-2 and increased VDVADase activity were observed in the hippocampus immediately after seizure termination.
  • Expression of RAIDD increased post-seizure, while RIP and TRADD levels remained unchanged.
  • Inhibition of caspase-2 blocked its activity but did not affect caspase-8 activity, DNA fragmentation, or neuronal death.

Conclusions:

  • Caspase-2 is activated in the hippocampus following seizures.
  • Despite caspase-2 activation, its inhibition does not prevent seizure-induced neuronal death.
  • Parallel caspase pathways likely contribute to or compensate for caspase-2 function in neuronal cell death.

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