Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain.
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-cerebro-ventricular 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 microM) also blocked 3NP-induced death of cultured striatal neurons. In vitro, zVAD inhibited purified mu-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.
Bizat
Nicolas
N
URA CEA-CNRS 2210, Service Hospitalier Frédéric Joliot and Program ImaGene, DRM, DSV, CEA, 4 place du Général Leclerc, 91401 Orsay, France.
Galas
Marie-Christine
MC
Jacquard
Carine
C
Boyer
Frédéric
F
Hermel
Jean-Michel
JM
Schiffmann
Serge N
SN
Hantraye
Philippe
P
Blum
David
D
Brouillet
Emmanuel
E
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D006816:Huntington Disease / Q000473:pathology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects; D009410:Nerve Degeneration / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009574:Nitro Compounds; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D011422:Propionates / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011480:Protease Inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013049:Spectrin
D002154:Calpain; D002352:Carrier Proteins; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D009842:Oligopeptides; D011422:Propionates; D011480:Protease Inhibitors; D013049:Spectrin; C103712:benzyloxycarbonyl-valyl-alanyl-aspartyl-fluoromethane; C015392:3-nitropropionic acid