Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells.
Hyperammonemia in neonates and infants causes irreversible damages in the developing CNS due to brain cell loss. Elucidating the mechanisms triggering ammonia-induced cell death in CNS is necessary for the development of neuroprotective strategies. We used reaggregated developing brain cell cultures derived from fetal rat telencephalon exposed to ammonia as an experimental model. Ammonia induced neuronal and oligodendroglial death, triggered apoptosis and activated caspases and calpain. Probably due to calpain activation, ammonia caused the cleavage of the cyclin-dependent kinase 5 activator, p35, to p25, the cdk5/p25 complex being known to lead to neurodegeneration. Roscovitine, a cdk5 inhibitor, protected neurons from ammonia-induced cell death. However, roscovitine also impaired axonal growth, probably through inhibition of the remaining cdk5/p35 activity, which is involved in neurite outgrowth. Thus, cdk5 appears as a promising therapeutic target for treating hyperammonemic newborns and infants, especially if one develops specific cdk5/p25 inhibitors.
Cagnon
Laurène
L
Inborn Errors of Metabolism, Clinical Chemistry Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.
Braissant
Olivier
O
D000641:Ammonia / Q000494:pharmacology*; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047468:Immunoprecipitation / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D016548:Prosencephalon / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D000641:Ammonia; D007770:L-Lactate Dehydrogenase; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain; D020169:Caspases