Cyclosporin A enhances colchicine-induced apoptosis in rat cerebellar granule neurons

被引:7
作者
Canudas, AM
Jordà, EG
Verdaguer, E
Jiménez, A
Sureda, FX
Rimbau, V
Camins, A
Pallàs, M
机构
[1] Univ Barcelona, Fac Farm, Unitat Farmacol & Farmacognosia, E-08028 Barcelona, Spain
[2] Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Farmacol, Tarragona 43201, Spain
关键词
cyclosporin A; colchicine; neurotoxicity; flavopiridol; roscovitine; Cdk5;
D O I
10.1038/sj.bjp.0705664
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 Cyclosporin A (CsA, 1-50 muM), 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 muM). 2 Flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), prevented the neurotoxic effects of colchicine plus CsA. At 0.1-5 muM, it also showed antiapoptotic effects, as revealed by propidium iodide staining, flow cytometry and counting of cell nuclei. 3 Roscovitine (25-50 muM), a selective cdk 1, 2 and 5 inhibitor, showed an antiapoptotic effect against colchicine- and colchicine plus CsA-induced apoptosis. 4 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. 5 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.
引用
收藏
页码:661 / 669
页数:9
相关论文
共 56 条
[21]   Pharmacological inhibitors of cyclin-dependent kinases [J].
Knockaert, M ;
Greengard, P ;
Meijer, L .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2002, 23 (09) :417-425
[22]   Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25 [J].
Kusakawa, G ;
Saito, T ;
Onuki, R ;
Ishiguro, K ;
Kishimoto, T ;
Hisanaga, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (22) :17166-17172
[23]  
Lau Lit-Fui, 2002, Current Topics in Medicinal Chemistry, V2, P395, DOI 10.2174/1568026024607526
[24]   Indirubins inhibit glycogen synthase kinase-3β and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease -: A property common to most cycline-dependent kinase inhibitors? [J].
Leclerc, S ;
Garnier, M ;
Hoessel, R ;
Marko, D ;
Bibb, JA ;
Snyder, GL ;
Greengard, P ;
Biernat, J ;
Wu, YZ ;
Mandelkow, EM ;
Eisenbrand, G ;
Meijer, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (01) :251-260
[25]   Neurotoxicity induces cleavage of p35 to p25 by calpain [J].
Lee, MS ;
Kwon, YT ;
Li, MW ;
Peng, JM ;
Friedlander, RM ;
Tsai, LH .
NATURE, 2000, 405 (6784) :360-364
[26]   Four deaths and a funeral:: From caspases to alternative mechanisms [J].
Leist, M ;
Jäättelä, M .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2001, 2 (08) :589-598
[27]  
Leventhal L, 2000, J COMP NEUROL, V425, P471, DOI 10.1002/1096-9861(20001002)425:4<471::AID-CNE1>3.0.CO
[28]  
2-U
[29]   Acute exposure to methylmercury opens the mitochondrial permeability transition pore in rat cerebellar granule cells [J].
Limke, TL ;
Atchison, WD .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2002, 178 (01) :52-61
[30]   Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons [J].
Mao, ZX ;
Wiedmann, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (43) :31102-31107