A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo.

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: Lichuan Yang, Shuei Sugama, Ronald P Mischak, Mahmoud Kiaei, Nicolas Bizat, Emmanuel Brouillet, Tong H Joh, M Flint Beal
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 17 Issue 2 Pg. 250-9 (Nov 2004) ISSN: 0969-9961 [Print] United States
• PMID: 15474362 (Publication Type: 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.)

Chemical References

• Amino Acid Chloromethyl Ketones
• BH3 Interacting Domain Death Agonist Protein
• Bid protein, mouse
• Bid protein, rat
• Carrier Proteins
• Caspase Inhibitors
• Dopamine Agents
• Enzyme Inhibitors
• Malonates
• Neurotoxins
• Nitro Compounds
• Propionates
• Quinolines
• quinoline-val-asp(OMe)-CH2-OPH
• malonic acid
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Calpain
• Casp8 protein, mouse
• Casp8 protein, rat
• Casp9 protein, mouse
• Casp9 protein, rat
• Caspase 8
• Caspase 9
• Caspases
• 3-nitropropionic acid

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (antagonists & inhibitors, pharmacology)
• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• BH3 Interacting Domain Death Agonist Protein
• Brain (drug effects)
• Calpain (metabolism)
• Carrier Proteins (chemistry, drug effects)
• Caspase 8
• Caspase 9
• Caspase Inhibitors
• Caspases (chemistry, drug effects)
• Corpus Striatum (drug effects, pathology)
• Dopamine Agents (poisoning)
• Enzyme Inhibitors (pharmacology)
• Male
• Malonates (antagonists & inhibitors, poisoning)
• Mesencephalon (drug effects, enzymology)
• Mice
• Neurotoxins (antagonists & inhibitors)
• Nitro Compounds
• Propionates (antagonists & inhibitors, poisoning)
• Quinolines (pharmacology)
• Rats
• Rats, Inbred Lew
• Rats, Sprague-Dawley