Tags

Type your tag names separated by a space and hit enter

Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain.
Neuropharmacology. 2005 Oct; 49(5):695-702.N

Abstract

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.

Authors+Show Affiliations

URA CEA-CNRS 2210, Service Hospitalier Frédéric Joliot and Program ImaGene, DRM, DSV, CEA, 4 place du Général Leclerc, 91401 Orsay, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15998526

Citation

Bizat, Nicolas, et al. "Neuroprotective Effect of zVAD Against the Neurotoxin 3-nitropropionic Acid Involves Inhibition of Calpain." Neuropharmacology, vol. 49, no. 5, 2005, pp. 695-702.
Bizat N, Galas MC, Jacquard C, et al. Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain. Neuropharmacology. 2005;49(5):695-702.
Bizat, N., Galas, M. C., Jacquard, C., Boyer, F., Hermel, J. M., Schiffmann, S. N., Hantraye, P., Blum, D., & Brouillet, E. (2005). Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain. Neuropharmacology, 49(5), 695-702.
Bizat N, et al. Neuroprotective Effect of zVAD Against the Neurotoxin 3-nitropropionic Acid Involves Inhibition of Calpain. Neuropharmacology. 2005;49(5):695-702. PubMed PMID: 15998526.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effect of zVAD against the neurotoxin 3-nitropropionic acid involves inhibition of calpain. AU - Bizat,Nicolas, AU - Galas,Marie-Christine, AU - Jacquard,Carine, AU - Boyer,Frédéric, AU - Hermel,Jean-Michel, AU - Schiffmann,Serge N, AU - Hantraye,Philippe, AU - Blum,David, AU - Brouillet,Emmanuel, PY - 2005/01/11/received PY - 2005/04/25/revised PY - 2005/04/28/accepted PY - 2005/7/7/pubmed PY - 2005/11/1/medline PY - 2005/7/7/entrez SP - 695 EP - 702 JF - Neuropharmacology JO - Neuropharmacology VL - 49 IS - 5 N2 - 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. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/15998526/Neuroprotective_effect_of_zVAD_against_the_neurotoxin_3_nitropropionic_acid_involves_inhibition_of_calpain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(05)00184-X DB - PRIME DP - Unbound Medicine ER -