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Cyclosporin A enhances colchicine‐induced apoptosis in rat cerebellar granule neurons
Author(s) -
Canudas Anna Maria,
Jordà Elvira G,
Verdaguer Ester,
Jiménez Andrés,
Sureda Francesc Xavier,
Rimbau Víctor,
Camins Antoni,
Pallàs Mercè
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705664
Subject(s) - colchicine , apoptosis , neurotoxicity , propidium iodide , pharmacology , cyclin dependent kinase 5 , cyclin dependent kinase , biology , chemistry , programmed cell death , toxicity , cell cycle , biochemistry , cyclin dependent kinase 2 , genetics , organic chemistry
Cyclosporin A (CsA, 1–50 μ M ), an immunosuppressive drug with known neurotoxic effects, did not decrease the viability of primary cultures of rat cerebellar granule neurons (CGN) or induce apoptotic features. However, CsA specifically enhanced the cytotoxicity and apoptosis induced by colchicine (1 μ M ). Flavopiridol, an inhibitor of cyclin‐dependent kinases (CDKs), prevented the neurotoxic effects of colchicine plus CsA. At 0.1–5 μ M , it also showed antiapoptotic effects, as revealed by propidium iodide staining, flow cytometry and counting of cell nuclei. Roscovitine (25–50 μ M ), a selective cdk1, 2 and 5 inhibitor, showed an antiapoptotic effect against colchicine‐ and colchicine plus CsA‐induced apoptosis. CsA increased the expression of cdk5 and cdk5/p25 mediated by colchicine, a CDK involved in neuronal apoptosis. After treatment of CGN with colchicine plus CsA, the changes in the p25/p35 ratio pointed to cdk5 activation. Immunohistochemical results showed a nuclear localization of cdk5 after neurotoxic treatment, which was prevented by cdk inhibitors. Thus, we propose a new mechanism of modulation of CsA neurotoxicity mediated by cdk5.British Journal of Pharmacology (2004) 141 , 661–669. doi: 10.1038/sj.bjp.0705664