RT Journal Article
SR Electronic
T1 Inhibition of Cell Cycle Pathway by Flavopiridol Promotes Survival of Cerebellar Granule Cells after an Excitotoxic Treatment
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 609
OP 616
DO 10.1124/jpet.103.057497
VO 308
IS 2
A1 Ester Verdaguer
A1 Andrés Jiménez
A1 Anna M. Canudas
A1 Elvira G. Jordà
A1 F. Xavier Sureda
A1 Mercè Pallàs
A1 Antoni Camins
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/609.abstract
AB Kainic acid (KA)-induced neuronal damage and the protective effects of flavopiridol were studied in primary cultures of rat cerebellar granule cells (CGNs). When neurons were treated with 500 μM KA, the percentage of cells with condensed nuclei measured by nuclear counting increased by up to 55%. After flavopiridol treatment, an antitumoral drug that is a broad inhibitor of cyclin-dependent kinases, the percentage of condensed nuclei decreased by up to 26%. Furthermore, this KA-mediated cell death was only partially dependent on the activation of the initiator caspase-9 and the effector caspases-3 and -6. This argues for a minor role of caspases in the intracellular pathway leading to KA-induced programmed cell death in CGNs. We examined the possible implication of cell cycle proteins in KA-induced neurotoxicity. We found an increase in the expression of proliferating cell nuclear antigen and E2F-1, two proteins implicated in S-phase, by Western blot. KA increased bromodeoxyuridine incorporation in CGNs, a marker of cell proliferation, and flavopiridol attenuated this effect. These results indicated that flavopiridol decreased the expression of cell cycle markers in CGNs after KA treatment. Flavopiridol might thus be used as a preventive agent against neurodegenerative diseases associated with cell cycle activation. The American Society for Pharmacology and Experimental Therapeutics