A novel systemically active caspase inhibitor attenuates the toxicities of MPTP, malonate, and 3NP in vivo.
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.
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.
Lichuan
L
Yang
Shuei
S
Sugama
Ronald P
RP
Mischak
Mahmoud
M
Kiaei
Nicolas
N
Bizat
Emmanuel
E
Brouillet
Tong H
TH
Joh
M Flint
MF
Beal
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D001921:Brain / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000187:drug effects; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D015259:Dopamine Agents / Q000506:poisoning*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008314:Malonates / Q000037:antagonists & inhibitors* / Q000506:poisoning; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D009574:Nitro Compounds; D011422:Propionates / Q000037:antagonists & inhibitors* / Q000506:poisoning; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
D000590:Amino Acid Chloromethyl Ketones; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; C494816:Bid protein, rat; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D008314:Malonates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH; C030290:malonic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D002154:Calpain; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C015392:3-nitropropionic acid