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Journal ArticleDOI

21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils.

01 Aug 1988-Stroke (American Heart Association, Inc.)-Vol. 19, Iss: 8, pp 997-1002
TL;DR: It is shown that U74006F can improve survival and attenuate neuronal necrosis in a severe brain ischemia model and comparison of neuronal densities in the ischemic hemisphere with those in the contralateral nonischemic hemisphere revealed significant neuronal preservation.
Abstract: U74006F (21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione, monomethane sulfonate) is a novel and potent inhibitor of central nervous system tissue lipid peroxidation that is devoid of classical steroid hormonal activities. Its possible efficacy in attenuating postischemic mortality and neuronal necrosis was examined in gerbils following 3-hour unilateral carotid artery occlusion. Male Mongolian gerbils received two intraperitoneal injections of either vehicle or U74006F (3 or 10 mg/kg), the first injection 10 minutes before and the second injection at the end of the 3-hour ischemic episode. In an initial series of experiments, vehicle-treated gerbils displayed 60.9% (14 of 23) survival 24 hours after ischemia, which decreased to 34.8% (8 of 23) at 48 hours. In contrast, the 10 mg/kg U74006F-treated group showed 86.7% (13 of 15) survival at 24 hours (p less than 0.15 vs. vehicle) and 80.0% (12 of 15) survival at 48 hours (p less than 0.02). In a second series, neurons in the hippocampal CA1 subfield and the medial and lateral cerebral cortex were counted in gerbils surviving 24 hours after unilateral carotid artery occlusion. Comparison of neuronal densities in the ischemic hemisphere with those in the contralateral nonischemic hemisphere revealed significant neuronal preservation in all three brain regions of 10 mg/kg i.p. x 2 U74006F-treated gerbils. Our results show that U74006F can improve survival and attenuate neuronal necrosis in a severe brain ischemia model.(ABSTRACT TRUNCATED AT 250 WORDS)
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TL;DR: *Department of Neurophysiology, Institute of Physiology, Medical Faculty, Ruhr-Universitlt Bochum, and MRC Anatomical Neuropharmacology Unit, _ Department of Pha-rmacology, University of Oxford, Oxford, U.K.R.G.

875 citations

Journal ArticleDOI
TL;DR: Data support the possibility that NMDA receptor-mediated, Ca(2+)-dependent uncoupling of neuronal mitochondrial electron transport may contribute to the oxidative stress initiated by glutamate exposure.
Abstract: Increasing evidence suggests that glutamate neurotoxicity is partly mediated by reactive oxygen species, formed as a consequence of several processes, including arachidonic acid metabolism and nitric oxide production. Here we used an oxidation-sensitive indicator, dihydrorhodamine 123, in combination with confocal microscopy, to examine the hypothesis that electron transport by neuronal mitochondria may be an important source of glutamate-induced reactive oxygen species (ROS). Exposure to NMDA, but not kainate, ionomycin, or elevated potassium stimulated oxygen radical production in cultured murine cortical neurons, demonstrated by oxidation of nonfluorescent dihydrorhodamine 123 to fluorescent rhodamine 123. Electron paramagnetic resonance spectroscopy studies using 5,5-dimethyl-1- pyrroline-N-oxide (DMPO) as a radical-trapping agent, also showed production of ROS by cortical neurons after NMDA but not kainate exposure. NMDA-induced ROS production depended on extracellular Ca2+, and was not affected by inhibitors of nitric oxide synthase or arachidonic acid metabolism. The increased production of ROS was blocked by inhibitors of mitochondrial electron transport, rotenone or antimycin, and mimicked by the electron transport uncoupler, carbonyl cyanide p-trifluoromethoxyphenylhydrazone. These data support the possibility that NMDA receptor-mediated, Ca(2+)-dependent uncoupling of neuronal mitochondrial electron transport may contribute to the oxidative stress initiated by glutamate exposure.

784 citations


Cites background from "21-Aminosteroid lipid peroxidation ..."

  • ...Further, antioxidant therapy is neuroprotective in trauma and ischemia (Saunders et al., 1987; Hall et al., 1988; Liu et al., 1989)....

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Journal ArticleDOI
TL;DR: The possibility of new therapies for cerebral hypoxia directed at glutamate-mediated injury mechanisms are commented on, based on recent information suggesting that central neurotransmitter mechanisms may play an important role in the pathogenesis of hypoxic neuronal death.
Abstract: The apoplexy of Hippocrates’ time remains with us today, unchanged and untreated We call this syndrome of acute brain damage “stroke”; we know that it most commonly reflects localized tissue hypoxia attributable to reduced blood flow (ischemia) Focal hypoxia-ischemia also occurs in such contexts as traumatic insults, or cerebral hemorrhages, while global hypoxia-ischemia occurs in cardiac arrest, near-drowning, and carbon monoxide poisoning The centuries since Thomas Willis, Johann Wepfer, and Giovanni Morgagni have brought precise definition of cerebral vascular anatomy and the neurological consequences of focal brain lesions, permitting full comprehension of functional deficits; we can prognosticate with sad accuracy But the medical management of stroke patients in 1990 is still the management of symptoms and associated conditions Despite its status as a major worldwide cause of death and disability, we are no more able than Hippocrates to treat cerebral hypoxia itself Nevertheless, hope for the development of effective therapy has endured, and in the last few years has been encouraged by the emergence of some promising strategies for reducing the brain’s intrinsic susceptibility to hypoxic insults These tissuelevel approaches, sometimes referred to as “parenchymal” approaches to distinguish them from other strategies aimed at influencing blood how, are based on recent information suggesting that central neurotransmitter mechanisms, especially those related to the excitatory neurotransmitter glutamate, may play an important role in the pathogenesis of hypoxic neuronal death (Meldrum, 1985; Rothman and Olney, 1986; Choi, 1988b) In this essay I will comment on the possibility of new therapies for cerebral hypoxia directed at glutamate-mediated injury mechanisms, and will briefly mention some other potential approaches Glutamate and hypoxic neuronal injury The brain is critically dependent on its blood flow for a continuous supply of oxygen and glucose The oscillations of the electroencephalogram cease within seconds of cardiac arrest, and only a few minutes of severe ischemia can induce the selective degeneration of certain neuronal populations, including pyramidal neurons in the CA1 region of the hippocampal formation, striatal medium-sized neurons, neocortical neurons in layers 3,

687 citations

Journal ArticleDOI
TL;DR: Current understanding of oxygen radical mechanisms as they relate to the brain during ischemia and reperfusion is addressed and lipid-soluble antioxidants appear more efficacious because of their ability to cross the blood-brain barrier and their presence in membrane structures where peroxidative reactions can be halted.
Abstract: This review addresses current understanding of oxygen radical mechanisms as they relate to the brain during ischemia and reperfusion. The mechanism for radical production remains speculative in large part because of the difficulty of measuring radical species in vivo. Breakdown of lipid membranes during ischemia leads to accumulation of free fatty acids. Decreased energy stores during ischemia result in the accumulation of adenine nucleotides. During reperfusion, metabolism of free fatty acids via the cyclooxygenase pathway and metabolism of adenine nucleotides via the xanthine oxidase pathway are the most likely sources of oxygen radicals. Although leukocytes have been found to accumulate in some models of ischemia and reperfusion, their mechanistic role remains in question. Therapeutic strategies aimed at decreasing brain injury have included administration of radical scavengers at the time of reperfusion. Efficacy of traditional oxygen radical scavengers such as superoxide dismutase and catalase may be limited by their inability to cross the blood-brain barrier. Lipid-soluble antioxidants appear more efficacious because of their ability to cross the blood-brain barrier and because of their presence in membrane structures where peroxidative reactions can be halted.

643 citations

Journal ArticleDOI
TL;DR: Treatment with antioxidants may theoretically act to prevent propagation of tissue damage and improve both the survival and neurological outcome of acute central nervous system (CNS) injury.
Abstract: Free radicals are highly reactive molecules generated predominantly during cellular respiration and normal metabolism. Imbalance between cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress (OS). OS has been implicated as a potential contributor to the pathogenesis of acute central nervous system (CNS) injury. After brain injury by ischemic or hemorrhagic stroke or trauma, the production of reactive oxygen species (ROS) may increase, sometimes drastically, leading to tissue damage via several different cellular molecular pathways. Radicals can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., DNA), leading to subsequent cell death by modes of necrosis or apoptosis. The damage can become more widespread due to weakened cellular antioxidant defense systems. Moreover, acute brain injury increases the levels of excitotoxic amino acids (such as glutamate), which also produce ROS, thereby promoting parenchymatous destruction. Therefore, treatment with antioxidants may theoretically act to prevent propagation of tissue damage and improve both the survival and neurological outcome. Several such agents of widely varying chemical structures have been investigated as therapeutic agents for acute CNS injury. Although a few of the antioxidants showed some efficacy in animal models or in small clinical studies, these findings have not been supported in comprehensive, controlled trials in patients. Reasons for these equivocal results may include, in part, inappropriate timing of administration or suboptimal drug levels at the target site in CNS. Better understanding of the pathological mechanisms of acute CNS injury would characterize the exact primary targets for drug intervention. Improved antioxidant design should take into consideration the relevant and specific harmful free radical, blood brain barrier (BBB) permeability, dose, and time administration. Novel combinations of drugs providing protection against various types injuries will probably exploit the potential synergistic effects of antioxidants in stroke.

570 citations


Cites background from "21-Aminosteroid lipid peroxidation ..."

  • ...It improved both 24- and 48-h survival in gerbils subjected to 3 h of unilateral carotid occlusion (Hall et al., 1988)....

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References
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Journal ArticleDOI
01 Sep 1978-Stroke
TL;DR: The possibility that cerebral ischemia may initiate a series of pathological free radical reactions within the membrane components of the CNS was investigated in the cat and there was a progressive decrease in the amount of detectable ascorbic acid following middle cerebral artery occlusion.
Abstract: The possibility that cerebral ischemia may initiate a series of pathological free radical reactions within the membrane components of the CNS was investigated in the cat. The normally occurring electron transport radicals require adequate molecular oxygen for orderly transport of electrons and protons. A decrease in tissue oxygen removes the controls over the electron transport radicals, and allows them to initiate pathologic radical reactions among cell membranes such as mitochondria. Pathologic radical reactions result in multiple products, each of which may be present in too small a concentration to permit their detection at early time periods. It is possible to follow the time course, however, by the decrease of a major antioxidant as it is consumed by the pathologic radical reactions. For this reason, ascorbic acid was measured in ischemic and control brain following middle cerebral artery occlusion. There was a progressive decrease in the amount of detectable ascorbic acid ranging from 25% at 1 hour to 65% at 24 hours after occlusion. The reduction of this normally occurring antioxidant and free radical scavenger may indicate consumption of ascorbic acid in an attempt to quench pathologic free radical reactions occurring within the components of cytomembranes.

570 citations

Journal ArticleDOI
TL;DR: Two representative compounds from a novel chemical series of potent inhibitors of lipid peroxidation are described and one of the compounds, U74500A, may act as a membrane localized chelator of iron.

454 citations

Journal ArticleDOI
TL;DR: The present study was undertaken to determine the reproducibility of the modcl and to document for the first time the natural cc)urse of events following ligation, which can then be used to evaluate the efficiency of theraupeutic agents in modifying morbidity and mortality.
Abstract: The study of any disease process is greatly advanced by the availability of an animal model for laboratory investigation. Cerebral infarction has been difficult to reproduce experimentally because of the efficiency of the collateral circulation. It has recently been demonstrated that a unilateral hemispheric infarction can be produced i n the Mongolian gerbil (Meriones unguiculatus) by ligation of a single common carotid artery.' This unique characteristic of the gerbil is due to an absence of connecting a r t e r i e s between the basilar and carotid systems.* The present study was undertaken to determine the reproducibility of the modcl and to document for the first time the natural cc)urse of events following ligation. These base-line data can then be used to evaluate the efficiency of theraupeutic agents in modifying morbidity and mortality.

283 citations

Journal ArticleDOI
TL;DR: The observation that the effect is highly focal and not generalized throughout the brain suggests that special conditions of reperfusibility and reoxygenation must be satisfied for lipid peroxidation to be detectable in an ischemic milieu.
Abstract: It has been hypothesized that ischemia, followed by reperfusion, facilitates peroxidative free-radical chain processes in brain. To resolve this question, rats were subjected to reversible global ischemia. From coronal sections of brains frozen in situ, small (ca. 2 mg) amounts of tissue were sampled from neocortex, hippocampus, and thalamus of both cerebral hemispheres of four groups of rats exposed to 30 min cerebral ischemia followed by 0, 30, 60, and 240 min of reperfusion, and from a control group subjected to the same operative procedures, except for the induction of ischemia. Heptane-solubilized total lipid extracts from these samples were analyzed spectroscopically in the 190-330 nm range for content of isolated (nonconjugated) double bonds and of conjugated diene structures; the latter are formed from isolated double bonds during peroxidation of unsaturated fatty acids. Spectra derived from tissue regions of rats subjected to ischemia, or ischemia followed by reperfusion, were compared to averaged, region-specific control spectra and were normalized to the original content of isolated double bonds in the peroxidized samples. The resultant difference spectra were analyzed in terms of ratios of conjugated diene concentration to the concentration of isolated double bonds originally at risk in the specific tissue zones considered. The peak representing conjugated diene formation was centered at 238 +/- 1 nm and was usually well resolved when the molar ratio [conjugated diene]/[isolated double bonds], expressed as a percentage [( CD]/[IDB]), was greater than 0.25%.(ABSTRACT TRUNCATED AT 250 WORDS)

277 citations