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Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells

Laurène Cagnon1, Olivier Braissant

  • 1Inborn Errors of Metabolism, Clinical Chemistry Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.

Neurobiology of Disease
|August 30, 2008
PubMed

Insights

Hyperammonemia causes brain cell death in infants. Inhibiting cyclin-dependent kinase 5 (cdk5) shows promise for neuroprotection, but requires specific drug development to avoid side effects.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Toxicology

Background:

  • Hyperammonemia in neonates and infants leads to irreversible central nervous system (CNS) damage.
  • Understanding ammonia-induced cell death mechanisms is crucial for developing neuroprotective therapies.

Purpose of the Study:

  • To investigate the mechanisms of ammonia-induced cell death in developing CNS.
  • To evaluate cyclin-dependent kinase 5 (cdk5) as a potential therapeutic target.

Main Methods:

  • Used reaggregated developing rat brain cell cultures exposed to ammonia.
  • Analyzed apoptosis, caspases, calpain activation, and p35 cleavage to p25.
  • Tested the effects of roscovitine, a cdk5 inhibitor.

Main Results:

  • Ammonia induced neuronal and oligodendroglial death via apoptosis and caspase/calpain activation.
  • Ammonia promoted p35 cleavage to p25, forming a neurotoxic cdk5/p25 complex.
  • Roscovitine protected neurons but impaired axonal growth.

Conclusions:

  • cdk5 is implicated in ammonia-induced neurodegeneration.
  • Targeting the cdk5/p25 complex may offer neuroprotection in hyperammonemia.
  • Development of specific cdk5/p25 inhibitors is warranted to mitigate side effects.

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