[en] In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
Disciplines :
Neurologie
Auteur, co-auteur :
Schulz, Jörg B.; Experimental Neuropharmacology Laboratory, Department of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany.jeorg.b.schulz@uni-tuebingen.de
Weller, Michael; Exp. Neuropharmacology Laboratory, Department of Neurology, University of Tübingen, D-72076 Tübingen, Germany
Matthews, Russell T.; Exp. Neuropharmacology Laboratory, Department of Neurology, University of Tübingen, D-72076 Tübingen, Germany ; Neurochemistry Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
HENEKA, Michael ; Exp. Neuropharmacology Laboratory, Department of Neurology, University of Tübingen, D-72076 Tübingen, Germany
Groscurth, Peter; Institute of Anatomy, Division of Cell Biology, University of Zurich, Ch-8057 Zürich, Switzerland
This work was supported by grants from the Deutsche Forschungsge-meinschaft (Schu 932/2-1) and the fortüne program of the University Tübingen. We thank L. Dumitrescu and I. Müller for excellent technical assistance.
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