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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Boucher, Mathieu Colucci, John Flückiger, Jean-pierre Ashdown, Helen Robertson, George S. Ng, Gordon Y. K. Bureau, Yves O'donnell, Ruth Degen, Sarah Nicholson, Donald W. Han, Yongxin Zhu, Yanxia Zamboni, Robert Rigby, Michael Giroux, André Xanthoudakis, Steven Tang, Keith Pikounis, Bill Tam, John Toulmond, Sylvie Roy, Sophie |
| Description | Author Affiliation: Toulmond S ( Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, H9H 3L1, Canada. sylvie_toulmond@merck.com) |
| Abstract | 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. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 141 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2004-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Caspase Inhibitors Enzyme Inhibitors Pharmacology Huntington Disease Chemically Induced Drug Therapy Malonates Neuroprotective Agents Oxadiazoles Pyrazines Animals Autoradiography Caspase 3 Cell Count Cell Death Drug Effects Diffusion Dizocilpine Maleate Pharmacokinetics Enzyme-Linked Immunosorbent Assay Excitatory Amino Acid Antagonists Half-Life Pathology Neostriatum Neurons Rats, Sprague-Dawley |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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