Neuroprotective effects of M826, a reversible caspase-3 inhibitor, in the rat malonate model of Huntington's disease.
1. Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase-3-specific inhibitor, M826 (3-([(2S)-2-[5-tert-butyl-3-[[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]amino]-2-oxopyrazin-1(2H)-yl]butanoyl]amino)-5-[hexyl(methyl)amino]-4-oxopentanoic acid), in a rat malonate model of HD. 2. Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [(3)H]M826 indicated that the compound diffused within the entire striatum. The elimination half-life (T(1/2)) of M826 in the rat striatum was 3 h. 3. I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase-3 in the ipsilateral striatum. 4. Inhibition of active caspase-3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801. 5. These data provide in vivo proof-of-concept of the neuroprotective effects of reversible caspase-3 inhibitors in a model of malonate-induced striatal injury in the adult rat.
Toulmond
Sylvie
S
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, H9H 3L1, Canada. sylvie_toulmond@merck.com
Tang
Keith
K
Bureau
Yves
Y
Ashdown
Helen
H
Degen
Sarah
S
O'Donnell
Ruth
R
Tam
John
J
Han
Yongxin
Y
Colucci
John
J
Giroux
André
A
Zhu
Yanxia
Y
Boucher
Mathieu
M
Pikounis
Bill
B
Xanthoudakis
Steven
S
Roy
Sophie
S
Rigby
Michael
M
Zamboni
Robert
R
Robertson
George S
GS
Ng
Gordon Y K
GY
Nicholson
Donald W
DW
Flückiger
Jean-Pierre
JP
D000818:Animals; D001345:Autoradiography; D053148:Caspase 3; D061945:Caspase Inhibitors; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D004058:Diffusion; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006207:Half-Life; D006816:Huntington Disease / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008314:Malonates; D017072:Neostriatum / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D010069:Oxadiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C465343:M 826 compound; D008314:Malonates; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D011719:Pyrazines; D016291:Dizocilpine Maleate; C505410:Casp3 protein, rat; D053148:Caspase 3