The Platelet-Activating Factor Antagonist BN 52021 Attenuates Hypoxic-Ischemic Brain Injury in the Immature Rat

Liu, Xiao Hong; Eun, Baik Lin; Silverstein, Faye S.; Barks, John

doi:10.1203/00006450-199612000-00004

Cited by 68 publications

(43 citation statements)

References 39 publications

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“…The results indicate that administration of 0.01 or 0.1 mg/kg of TS-011 significantly reduced infarct volume in rats following transient occlusion of the MCA by 35%. In this regard, blockade of 20-HETE formation with TS-011 is as or more effective than N-methyl-D-aspartate (Liu et al, 1996a), endothelin (Patel et al, 1996), leukotriene (Aspey et al, 1997), platelet-activating factor (Liu et al, 1996b), and Ca channel blockers (Shino et al, 1991) in reducing infarct size in this model. Effect of TS-011 on minimizing infarct volume was stronger in cortex than subcortex area.…”

Section: Discussionmentioning

confidence: 77%

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

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The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-NЈ-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC 50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC 50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 M. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.Each year, 750,000 strokes occur in the United States. Approximately 80% of the strokes are ischemic, and 20% are hemorrhagic. Hemorrhagic stroke commonly occurs after rupture of aneurysms or head trauma. There is an initial period of cerebral ischemia lasting several hours due to a rise in cerebral spinal fluid (CSF) pressure and acute cerebral vasospasm. One-half of the patients that survive later develop delayed vasospasm. The mortality in the 1st month hovers around 50%. The majority of deaths (Ͼ60%) occur during the first 2 days and is associated with ischemic brain injury (Broderick et al., 1994). The factors that contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH) remain uncertain.Ischemic strokes are caused by blockage of cerebral arteries. In the ischemic neuronal tissue, there is depletion of

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Section: Discussionmentioning

confidence: 77%

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

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“…Another possibility for therapeutic intervention would involve disruption of TNF-␣-induced production or release of PAF [53]. A wide variety of PAF receptor antagonists and a recombinant PAF acetylhydrolase (responsible for catabolism of brain PAF) are also available, some of which may cross the blood-brain barrier [54,55]. Antagonism of PAF-mediated signal transduction is important because PAF can activate NMDA receptors [22].…”

Section: Therapeutic Strategies For Hiv-1 Infection In the Developingmentioning

confidence: 99%

HIV-1-induced neuronal injury in the developing brain

Epstein

Gelbard

1999

Journal of Leukocyte Biology

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HIV-1 infection of the nervous system causes neuronal injury and death, resulting in cognitive, motor, and behavioral dysfunction in both adults and children. In infants a characteristic feature of HIV-1 infection is impaired brain growth resulting in secondary microcephaly with onset between 2 and 4 months of age. This post-natal period of brain development is particularly vulnerable to excitotoxic neuronal injury due to the active synaptogenesis and pruning that takes place at this age associated with over-expression of excitatory amino acid (EAA) receptors. HIV-1 infection of brain microglia and perivascular macrophages results in chronic inflammation manifest pathologically as diffuse microglial activation and reactive astrogliosis. Several inflammatory products of activated microglia, including tumor necrosis factor ␣ (TNF-␣) and platelet-activating factor (PAF) have been shown to act as neuronal toxins. This toxic effect can be antagonized by blocking NMDA (or AMPA) glutamate receptors, suggesting that (weak) excitotoxicity leads to oxidative stress, neuronal injury, and apoptosis. HIV-1 infection and chronic inflammation may also contribute disruption of the blood-brain barrier and could result in further entry into the CNS of toxic viral or cellular products or additional HIV-1-infected cells. We hypothesize that prolonged microglial activation during HIV-1 infection underlies the neuronal injury and impaired brain growth in affected infants. Further investigation of the interaction between HIV-1-infected/activated microglia and developing neurons seems warranted. The current understanding of HIV neuropathogenesis implies that therapeutic strategies should target the sustained immune activation in microglia, attempt to repair the integrity of the blood-brain barrier, and provide ''neuroprotection'' from excitotoxic neuronal injury. J. Leukoc. Biol. 65: 453-457; 1999.

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“…Previous studies suggest that at least some of the deleterious effects of PAF in neonatal cerebral hypoxia-ischemia are mediated via the synaptic membrane PAF receptor (17). The present study was designed to test the hypothesis that PAF could also mediate hypoxic-ischemic brain damage via the microsomal PAF binding site.…”

mentioning

confidence: 99%

“…In mature animals, most reports indicate that PAF receptor antagonist treatment attenuates cerebral ischemic damage (13)(14)(15)(16). Several recent studies implicate PAF as a mediator of ischemic injury in the neonatal brain (12,17).…”

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confidence: 99%

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Platelet-Activating Factor Antagonist BN 50730 Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

2001

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Platelet-activating factor (PAF) is a lipid derived from breakdown of cell membranes that is postulated to be a mediator of cerebral ischemic injury. PAF regulates CNS gene transcription via intracellular binding sites. To test the hypothesis that PAF mediates CNS injury in part by modulating gene transcription, we evaluated the neuroprotective efficacy of the drug BN 50730, an antagonist of the intracellular (microsomal) CNS PAF binding site, in the neonatal rat model of unilateral cerebral hypoxiaischemia. Seven-day-old rats underwent right carotid ligation followed by a 2.5-h exposure to 8% O 2 , and were then treated with BN 50730 (2.5 or 25 mg/kg per dose) or vehicle, at 0 and 2 h after the end of hypoxia. Ipsilateral cortical, striatal, and hippocampal damage was quantitated either 5 d later, or at 5 wk after the insult. Treatment with BN 50730 resulted in approximately 60 -80% reduction in ipsilateral tissue loss at both times. Learning and memory were evaluated 5 wk after insult using the Morris Watermaze place navigation task. Severity of cortical and striatal damage correlated significantly with learning and memory deficits. These results support the hypothesis that PAF is a pathogenetic mediator of hypoxic-ischemic damage in the immature brain. Accumulating evidence suggests that PAF mediates its deleterious effects in the immature CNS via multiple mechanisms. PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator with distinct systemic and CNS actions. In the CNS, PAF is synthesized in neurons and microglia (1, 2), and PAF receptors are expressed predominantly in neurons and microglia and, to a lesser extent, on astrocytes and CNS endothelium (3-5). PAF has distinct neuronal actions, as a synaptic messenger, a transcriptional activator, and a critical determinant of normal brain development (6, 7). In addition to these CNS effects, PAF has potent proinflammatory systemic effects (8). PAF accumulates in ischemic CNS tissue in mature and immature animals (9 -12). In mature animals, most reports indicate that PAF receptor antagonist treatment attenuates cerebral ischemic damage (13-16). Several recent studies implicate PAF as a mediator of ischemic injury in the neonatal brain (12, 17).Brain PAF concentrations rise acutely after neonatal cerebral hypoxia-ischemia (12), most likely as a result of breakdown of membrane phospholipids. Treatment with the PAF receptor antagonist BN 52021 (ginkgolide B), beginning either before or immediately after hypoxia exposure, reduced hypoxicischemic brain injury in postnatal d 7 rats (17). Pretreatment with a Ginkgo biloba extract, which includes BN 52021, attenuated posthypoxic-ischemic PAF accumulation (12). These results suggest that PAF contributes to the pathogenesis of neonatal cerebral hypoxic-ischemic injury.PAF could mediate cerebral hypoxic-ischemic injury via either of two distinct neuronal PAF binding sites. Studies in adult rat cerebral cortex subcellular membrane fractions delineate distinct populations of neuronal PAF bind...

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The Platelet-Activating Factor Antagonist BN 52021 Attenuates Hypoxic-Ischemic Brain Injury in the Immature Rat

Cited by 68 publications

References 39 publications

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

HIV-1-induced neuronal injury in the developing brain

Platelet-Activating Factor Antagonist BN 50730 Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

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