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

Neurobiology of Disease
Laurène Cagnon, O Braissant

Abstract

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.

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Citations

Mar 11, 2011·Amino Acids·Olivier BraissantJoséphine Uldry
Oct 31, 2012·Journal of Inherited Metabolic Disease·Olivier BraissantCristina Cudalbu
Jun 23, 2010·Journal of Biomaterials Science. Polymer Edition·Yulin SongXiaoling Fu
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Nov 15, 2016·Analytical Biochemistry·Veronika RackayovaOlivier Braissant

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