Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain

被引:32
作者
Bizat, N
Galas, MC
Jacquard, C
Boyer, F
Hermel, JM
Schiffmann, SN
Hantraye, P
Blum, D
Brouillet, E
机构
[1] CEA, Serv Hosp Frederic Joliot, Dept Med Res, URA,CNRS 2210,Neuronal Death Grp, F-91406 Orsay, France
[2] CEA, DSV, DRM, Program ImaGene, F-91406 Orsay, France
[3] ULB Erasme, Neurophysiol Lab, B-1070 Brussels, Belgium
[4] INSERM, U422, F-59045 Lille, France
[5] ULB Erasme, Lab Neurochirurg Expt, B-1070 Brussels, Belgium
[6] ULB Erasme, IRIBHM, B-1070 Brussels, Belgium
关键词
neurodegeneration; succinate dehydrogenase; mitochondrial complex II inhibitor; calpain; caspase; calpain inhibitor; neuroprotection;
D O I
10.1016/j.neuropharm.2005.04.030
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The contribution of calpains and caspases to cell death has been widely studied using pharmacological inhibitors. Among them, the caspase inhibitor N-benzyloxycarbonyl-valyl-alanyl-aspartyl-fluoromethylketone (zVAD) has been used as a specific caspase inhibitor in nearly 1000 published studies. However, several studies showed that zVAD also behaves as a calpain inhibitor in peripheral cells. The effects of zVAD as a calpain inhibitor have never been assessed in neurodegeneration models. We examined here whether zVAD could reduce neurodegeneration in Huntington's disease models using the mitochondrial inhibitor 3-nitropropionic acid (3NP). In these models, 3NP toxicity has been shown to require calpain activation. In rats, intra-cerebroventricular infusion of zVAD significantly reduced 3NP-induced striatal degeneration, and decreased the 3NP-induced activation of calpain and calpain-dependent cleavage of fodrin. zVAD (100 mu M) also blocked 3NP-induced death of cultured striatal neurons. In vitro, zVAD inhibited purified g-calpain with high affinity (IC50 = 10 nM). The present data demonstrate that zVAD protects neurons against 3NP through calpain inhibition. This suggests that, in certain models of neuronal death where zVAD showed protective effects, caspases but also calpains may be involved. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:695 / 702
页数:8
相关论文
共 41 条
[11]   Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease [J].
Chen, M ;
Ona, VO ;
Li, MW ;
Ferrante, RJ ;
Fink, KB ;
Zhu, S ;
Bian, J ;
Guo, L ;
Farrell, LA ;
Hersch, SM ;
Hobbs, W ;
Vonsattel, JP ;
Cha, JHJ ;
Friedlander, RM .
NATURE MEDICINE, 2000, 6 (07) :797-+
[12]   The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction [J].
Chen, Q ;
Chai, YC ;
Mazumder, S ;
Jiang, C ;
Macklis, R ;
Chisolm, GM ;
Almasan, A .
CELL DEATH AND DIFFERENTIATION, 2003, 10 (03) :323-334
[13]   Early N-acetylaspartate depletion is a marker of neuronal dysfunction in rats and primates chronically treated with the mitochondrial toxin 3-nitropropionic acid [J].
Dautry, W ;
Vaufrey, F ;
Brouillet, E ;
Bizat, N ;
Henry, PG ;
Condé, F ;
Bloch, G ;
Hantraye, P .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (05) :789-799
[14]   Participation of Par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid [J].
Duan, WZ ;
Guo, ZH ;
Mattson, MP .
EXPERIMENTAL NEUROLOGY, 2000, 165 (01) :1-11
[15]   Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus [J].
Ekdahl, CT ;
Mohapel, P ;
Elmér, E ;
Lindvall, O .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 14 (06) :937-945
[16]   Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family [J].
Endres, H ;
Namura, S ;
Skimizu-Sasamata, M ;
Waeber, C ;
Zhang, L ;
Gómez-Isla, T ;
Hyman, BT ;
Moskowitz, MA .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1998, 18 (03) :238-247
[17]   Insulin growth factor-I protects against excitotoxicity in the rat striatum [J].
Escartin, C ;
Boyer, F ;
Bemelmans, AP ;
Hantraye, P ;
Brouillet, E .
NEUROREPORT, 2004, 15 (14) :2251-2254
[18]   Calpain activation in Huntington's disease [J].
Gafni, J ;
Ellerby, LM .
JOURNAL OF NEUROSCIENCE, 2002, 22 (12) :4842-4849
[19]   Death of cortical and striatal neurons induced by mitochondrial defect involves differential molecular mechanisms [J].
Galas, MC ;
Bizat, N ;
Cuvelier, L ;
Bantubungi, K ;
Brouillet, E ;
Schiffmann, SN ;
Blum, D .
NEUROBIOLOGY OF DISEASE, 2004, 15 (01) :152-159
[20]  
GREENE JG, 1995, J NEUROCHEM, V64, P430