Improved Therapeutic Window for Treatment of Histotoxic Hypoxia with a Free Radical Spin Trap

Schulz, Jörg B.; Matthews, R T; Jenkins, Bruce G.; Brar, Paul S.; Beal, M. Flint

doi:10.1038/jcbfm.1995.120

Cited by 55 publications

(25 citation statements)

References 26 publications

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“…Oxidative stress has been implicated in neuronal damage due to perturbations of energy metabolism insomuch as free radical-trapping agents ameliorate neuronal loss in models of hypoxia/ischemia [Cao and Phillis, 1994;Carney and Floyd, 1991;Phillis and Clough-Helfman, 1990;Schulz et al, 1995b;Yue et al, 1992]. These findings provide indirect evidence for a contribution by oxidative events to neuronal damage caused by impairment of energy metabolism.…”

Section: Introductionmentioning

confidence: 56%

“…Lazaroids were found to protect against cerebral ischemia in vivo [Hall et al, 1988]. Spin-trap agents such as PBN or DMPO, which inhibit lipid peroxidation or trap free radicals, attenuated neuronal loss in various models of hypoxia/ischemia [Cao and Phillis, 1994;Carney and Floyd, 1991;Phillis and Clough Helfman, 1990;Yue et al, 1992] or versus an intrastratial infusion of malonate in rats [Schulz et al, 1995b]. Consistent with this, the current studies demonstrate that the more potent and lipophilic cyclic variant of PBN, MDL 102,832 [Thomas et al, 1996], significantly attenuated the irreversible loss of dopamine neurons due to inhibition of succinate dehydrogenase by malonate.…”

Section: Discussionmentioning

confidence: 99%

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Excitotoxicity and Oxidative Stress during Inhibition of Energy Metabolism

Zeevalk¹,

Bernard²,

Sinha³

et al. 1998

Dev Neurosci

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Glutamate receptor involvement and oxidative stress have both been implicated in damage to neurons due to impairment of energy metabolism. Using two different neuronal in vitro model systems, an ex vivo chick retinal preparation and dopamine neurons in mesencephalic culture, the involvement and interaction of these events as early occurring contributors to irreversible neuronal damage have been examined. Consistent with previous reports, the early acute changes in the retinal preparation, as well as irreversible loss of dopamine neurons due to inhibition of metabolism, can be prevented by blocking NMDA receptors during the time of energy inhibition. Oxidative stress was suggested to be a downstream consequence and contributor to neuronal cell loss due to either glutamate receptor overstimulation or metabolic inhibition since trapping of free radicals with the cyclic nitrone spin-trapping agent MDL 102,832 (1 mM) attenuated acute excitotoxicity in the retinal preparation or loss of mesencephalic dopamine neurons due to either metabolic inhibition by the succinate dehydrogenase inhibitor, malonate, or exposure to excitotoxins. In mesencephalic culture, malonate caused an enhanced efflux of both oxidized and reduced glutathione into the medium, a significant reduction in total reduced glutathione and a significant increase in total oxidized glutathione at time points that preceded those necessary to cause toxicity. These findings provide direct evidence for early oxidative events occurring following malonate exposure and suggest that the glutathione system is important for protecting neurons during inhibition of energy metabolism. Consistent with this, lowering of glutathione by buthionine sulfoxamine (BSO) pretreatment greatly potentiated malonate toxicity in the mesencephalic dopamine population. In contrast, BSO pretreatment did not potentiate glutamate toxicity. This latter finding indicates dissimilarities in the type of oxidative stress that is generated by the two insults and suggests that the oxidative challenge during energy inhibition is not solely a downstream consequence of glutamate receptor overstimulation.

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Section: Introductionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Excitotoxicity and Oxidative Stress during Inhibition of Energy Metabolism

Zeevalk¹,

Bernard²,

Sinha³

et al. 1998

Dev Neurosci

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“…After striatal injections of malonate, the therapeutic window for treatment with lamotrigine and MK-801 was 1 and 2 h, respectively, whereas a free radical spin trap showed efficacy when administered up to 6 h after malonate injections (Schulz et al, 1995b). zVAD-fmk was effective when administered up to 9 h after striatal malonate injection.…”

Section: Discussionmentioning

confidence: 99%

“…Since the activation of caspases was not detectable earlier than 6 h after striatal malonate injection, we examined whether delayed treatment with zVAD-fmk also provided protection. We previously showed that the glutamate release inhibitor, lamotrigine, and the NMDA antagonist, MK-801, exert neuroprotective effects against malonate toxicity when administered within 1 and 2 h, respectively (Schulz et al, 1995b). Treatment with 1 mg zVAD-fmk attenuated the lesion volume produced by malonate when injected at 3, 6 and 9 h but not at 12 h after malonate injections ( Figure 8A).…”

Section: Time Course Of Malonate Histopathologymentioning

confidence: 99%

Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia

et al. 1998

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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-benzyloxycarbonylVal-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.

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“…Although 7-NI can inhibit MAO-B, raising the possibility that this inhibition by 7-NI may also contribute to the observed neuroprotection [62], MPTP neurotoxicity is attenuated by more specific neuronal NOS inhibitors such as S-methylthiocitrulline [63]. Administration of the succinate dehydrogenase inhibitors 3-nitropropionic acid or malonate in rats or mice produce striatal lesions and behavioral abnormalities, characteristics of Huntington's disease, associated with the generation of hydroxyl radicals and 3-nitrotyrosine [64]. Administration of 7-NI, S-methylthiocitrulline, L-NA or N G -nitro-L-arginine methyl ester (L-NAME) attenuated the toxicity of 3-nitropropionic acid and malonate [63 -67].…”

Section: Multi-author Review Articlementioning

confidence: 96%

Nitric oxide synthases: targets for therapeutic strategies in neurological diseases

Chabrier

Demerlé‐Pallardy

Auguet

1999

CMLS, Cell. Mol. Life Sci.

202

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Fax + 33 1 60 92 21 25 rious effects of NO derived from neuronal or inducible Abstract. Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features isoforms. New neuroprotective strategies have been leading to neuronal death in cerebral ischemia, trau-proposed with selective NOS inhibitors for the neuronal matic brain injury, Parkinson's disease, Huntington's (ARL17477) or the inducible (1400W) isoforms or with disease, Alzheimer's disease and amyotrophic lateral compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in sclerosis. Nitric oxide (NO) alone or in cooperation experimental ischemia-induced acute neuronal damage. with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of The efficacy of these new strategies is well established in NO synthase (NOS) inhibitors and mutant mice lacking acute neuronal injury but remains to be determined in each NOS isoform have provided evidence for the inju-more chronic neurological diseases.

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Improved Therapeutic Window for Treatment of Histotoxic Hypoxia with a Free Radical Spin Trap

Cited by 55 publications

References 26 publications

Excitotoxicity and Oxidative Stress during Inhibition of Energy Metabolism

Excitotoxicity and Oxidative Stress during Inhibition of Energy Metabolism

Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia

Nitric oxide synthases: targets for therapeutic strategies in neurological diseases

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