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Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia.
Cell Death Differ. 1998 Oct; 5(10):847-57.CD

Abstract

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.

Authors+Show Affiliations

Experimental Neuropharmacology Laboratory, Department of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany.jeorg.b.schulz@uni-tuebingen.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10203688

Citation

Schulz, J B., et al. "Extended Therapeutic Window for Caspase Inhibition and Synergy With MK-801 in the Treatment of Cerebral Histotoxic Hypoxia." Cell Death and Differentiation, vol. 5, no. 10, 1998, pp. 847-57.
Schulz JB, Weller M, Matthews RT, et al. Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. Cell Death Differ. 1998;5(10):847-57.
Schulz, J. B., Weller, M., Matthews, R. T., Heneka, M. T., Groscurth, P., Martinou, J. C., Lommatzsch, J., von Coelln, R., Wüllner, U., Löschmann, P. A., Beal, M. F., Dichgans, J., & Klockgether, T. (1998). Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. Cell Death and Differentiation, 5(10), 847-57.
Schulz JB, et al. Extended Therapeutic Window for Caspase Inhibition and Synergy With MK-801 in the Treatment of Cerebral Histotoxic Hypoxia. Cell Death Differ. 1998;5(10):847-57. PubMed PMID: 10203688.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. AU - Schulz,J B, AU - Weller,M, AU - Matthews,R T, AU - Heneka,M T, AU - Groscurth,P, AU - Martinou,J C, AU - Lommatzsch,J, AU - von Coelln,R, AU - Wüllner,U, AU - Löschmann,P A, AU - Beal,M F, AU - Dichgans,J, AU - Klockgether,T, PY - 1999/4/16/pubmed PY - 1999/4/16/medline PY - 1999/4/16/entrez SP - 847 EP - 57 JF - Cell death and differentiation JO - Cell Death Differ VL - 5 IS - 10 N2 - 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. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/10203688/Extended_therapeutic_window_for_caspase_inhibition_and_synergy_with_MK_801_in_the_treatment_of_cerebral_histotoxic_hypoxia_ L2 - https://doi.org/10.1038/sj.cdd.4400420 DB - PRIME DP - Unbound Medicine ER -