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A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo.
Neurobiol Dis. 2004 Nov; 17(2):250-9.ND

Abstract

Molecular machinery involved in apoptosis plays a role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Several caspase inhibitors, such as the well-known peptidyl inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone (zVADfmk), can protect neurons from apoptotic death caused by mitochondrial toxins. However, the poor penetrability of zVADfmk into brain and toxicity limits its use therapeutically. In the present study, a novel peptidyl broad-spectrum caspase inhibitor, Q-VD-OPH, which offers improvements in potency, stability, and toxicity over zVADfmk, showed significant protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3NP), and malonate toxicities. Q-VD-OPH significantly reduced dopamine depletion in striatum produced by MPTP administration and prevented MPTP-induced loss of dopaminergic neurons in the substantia nigra. It significantly reduced the size of striatal lesions produced by intrastriatal malonate injections and systemic administration of 3NP. Western blots performed on tissues from the midbrain following administration of MPTP or the striatum in 3NP-treated animals showed increases of the active forms of caspase-9 and caspase-8, as well as the caspase-8-mediated proapoptotic protein Bid, which were inhibited Q-VD-OPH treatment. These findings suggest that systematically active broad-spectrum caspase inhibitors maybe useful in the treatment of neurodegenerative diseases such as PD and HD.

Authors+Show Affiliations

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.No 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
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15474362

Citation

Yang, Lichuan, et al. "A Novel Systemically Active Caspase Inhibitor Attenuates the Toxicities of MPTP, Malonate, and 3NP in Vivo." Neurobiology of Disease, vol. 17, no. 2, 2004, pp. 250-9.
Yang L, Sugama S, Mischak RP, et al. A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo. Neurobiol Dis. 2004;17(2):250-9.
Yang, L., Sugama, S., Mischak, R. P., Kiaei, M., Bizat, N., Brouillet, E., Joh, T. H., & Beal, M. F. (2004). A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo. Neurobiology of Disease, 17(2), 250-9.
Yang L, et al. A Novel Systemically Active Caspase Inhibitor Attenuates the Toxicities of MPTP, Malonate, and 3NP in Vivo. Neurobiol Dis. 2004;17(2):250-9. PubMed PMID: 15474362.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo. AU - Yang,Lichuan, AU - Sugama,Shuei, AU - Mischak,Ronald P, AU - Kiaei,Mahmoud, AU - Bizat,Nicolas, AU - Brouillet,Emmanuel, AU - Joh,Tong H, AU - Beal,M Flint, PY - 2003/12/22/received PY - 2004/07/26/revised PY - 2004/07/28/accepted PY - 2004/10/12/pubmed PY - 2004/12/22/medline PY - 2004/10/12/entrez SP - 250 EP - 9 JF - Neurobiology of disease JO - Neurobiol Dis VL - 17 IS - 2 N2 - Molecular machinery involved in apoptosis plays a role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Several caspase inhibitors, such as the well-known peptidyl inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone (zVADfmk), can protect neurons from apoptotic death caused by mitochondrial toxins. However, the poor penetrability of zVADfmk into brain and toxicity limits its use therapeutically. In the present study, a novel peptidyl broad-spectrum caspase inhibitor, Q-VD-OPH, which offers improvements in potency, stability, and toxicity over zVADfmk, showed significant protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3NP), and malonate toxicities. Q-VD-OPH significantly reduced dopamine depletion in striatum produced by MPTP administration and prevented MPTP-induced loss of dopaminergic neurons in the substantia nigra. It significantly reduced the size of striatal lesions produced by intrastriatal malonate injections and systemic administration of 3NP. Western blots performed on tissues from the midbrain following administration of MPTP or the striatum in 3NP-treated animals showed increases of the active forms of caspase-9 and caspase-8, as well as the caspase-8-mediated proapoptotic protein Bid, which were inhibited Q-VD-OPH treatment. These findings suggest that systematically active broad-spectrum caspase inhibitors maybe useful in the treatment of neurodegenerative diseases such as PD and HD. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/15474362/A_novel_systemically_active_caspase_inhibitor_attenuates_the_toxicities_of_MPTP_malonate_and_3NP_in_vivo_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(04)00169-X DB - PRIME DP - Unbound Medicine ER -