Platelet‐Activating Factor Antagonist BN52021 Decreases Accumulation of Free Polyunsaturated Fatty Acid in Mouse Brain During Ischemia and Electroconvulsive Shock

Birkle, Dale L.; Kurian, Pawels; Braquet, P.; Bazán, Nicolás G.

doi:10.1111/j.1471-4159.1988.tb01175.x

Cited by 102 publications

(30 citation statements)

References 22 publications

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“…When concentrations remain elevated, PAF lipids can initiate caspase-dependent neurotoxicity through PAFR-dependent and PAFR-independent pathways (7,8,22). In this regard, PAFs are recognized as primary mediators of neuronal apoptosis in acquired immune deficiency syndrome dementia, encephalitis, epileptic seizure, and ischemia (8,22,23). In progressive neurodegenerative disorders, PAF concentrations increase as a result of en- Fig.…”

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confidence: 99%

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

Ryan

Harris

Carswell

et al. 2008

Journal of Lipid Research

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The platelet-activating factor (PAF) family of glycerophospholipids accumulates in damaged brain tissue following injury. Little is known about the role of individual isoforms in regulating neuronal survival. Here, we compared the neurotoxic and neuroprotective activities of 1-Ohexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C 16 -PAF) and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine (C 18 -PAF) in cerebellar granule neurons. We find that both C 16 -PAF and C 18 -PAF cause PAF receptor-independent death but signal through different pathways. C 16 -PAF activates caspase-7, whereas C 18 -PAF triggers caspase-independent death in PAF receptor-deficient neurons. We further show that PAF receptor signaling is either pro-or anti-apoptotic, depending upon the identity of the sn-1 fatty acid of the PAF ligand. Activation of the PAF G-protein-coupled receptor (PAFR) by C 16 -PAF stimulation is anti-apoptotic and inhibits caspase-dependent death. Activation of PAFR by C 18 -PAF is pro-apoptotic. These results demonstrate the importance of the long-chain sn-1 fatty acid in regulating PAF-induced caspase-dependent apoptosis, caspase-independent neurodegeneration, and neuroprotection in the presence or absence of the PAF

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confidence: 99%

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

Ryan

Harris

Carswell

et al. 2008

Journal of Lipid Research

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“…Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1)(2)(3)(4)(5)(6)(7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8,9).…”

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confidence: 99%

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Bonin¹,

Ryan²,

Migahed³

et al. 2004

Journal of Biological Chemistry

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Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by ϳ15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I ␣ 1 regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I ␣ 2 expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I ␣ 2 homodimer activity by reducing PAF-AH I ␣ 1 expression. These findings identify PAF-AH I ␣ 2 as a potent antiapoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1-7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8, 9). Although the majority of PAF effects are understood to be transduced by its G-protein-coupled receptor (PAFR) (10), PAFR signaling has been shown to be both pro-and anti-apoptotic. Ectopic PAFR expression exacerbates cell death induced by etoposide and mitomycin C but protects cells from tumor necrosis factor ␣, TRAIL, and extracellular PAF (6,7,11,12). These opposing effects likely depend upon the relative ratio of NF-B-dependent pro-and anti-apoptotic gene products elicited in different cell types in response to the combination of an external apoptotic inducer and PAF (6).Accumulating evidence points to additional PAF signaling pathways transduced independently of PAFR (11, 13-17). PAFR-negative cells undergo apoptosis when extracellular PAF concentrations reach 100 nM and necrosis when PAF levels e...

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“…The production of PAF is increased upon stimulation of PLA 2 , and PAF has been shown to activate PLA 2 activity in rabbit platelets, thus causing the degradation of the membrane phospholipids [21] . BN 52021 can decrease the accumulation of the polyunsaturated fatty acids and decrease diglycerol in ischemia-reperfusion brain, which suggests an inhibitory effect of BN 52021 on the PLA 2 activity [22] . Therefore, the protective effects of BN 52021 against IR-mediated myocardial injury might be associated with the inhibition of cellular PLA 2 activity.…”

Section: Discussionmentioning

confidence: 99%

Ginkgolide B Reduces the Degradation of Membrane Phospholipids to Prevent Ischemia/Reperfusion Myocardial Injury in Rats

et al. 2015

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Platelet-activating factor (PAF), a bioactive phospholipid, plays an important role in the integrity of the cellular membrane structure, and is involved in the pathogenesis of myocardial ischemia/reperfusion (IR) injuries. In this study, we tested the hypothesis that blockage of PAF receptor by BN 52021 (Ginkgolide B) can prevent IR-induced degradation of the myocardial membrane phospholipid, and deterioration of the cardiac function. Rat hearts in situ were subjected to 5 min ischemia and followed by 10 min reperfusion. Cardiac performances during periods of ischemia and reperfusion were monitored, and the amount of membrane phospholipids was analyzed. Myocardial total phospholipids, phosphatidylcholine, and phosphatidylethanolamine were decreased significantly in ischemia-reperfusion rat hearts compared with those of sham-operated rat hearts. Degradation of the membrane phospholipid was accompanied by the deterioration of cardiac functions and increase in serum lactate dehydrogenase (LDH) activity. BN 52021 (15 mg/kg), given by intravenous infusion 10 min prior to the left anterior descending coronary artery occlusion, reduced IR-related degradation of the myocardial phospholipids, the activity of serum LDH, and was concomitant with improvement of cardiac function. Furthermore, we demonstrated that the production of PAF was increased and BN 52021 decreased cellular damage in cultured anoxic cardiomyocytes. These results indicated that PAF antagonist BN 52021 has a protective effect against IR-induced myocardial dysfunction and degradation of the membrane phospholipids.

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Platelet‐Activating Factor Antagonist BN52021 Decreases Accumulation of Free Polyunsaturated Fatty Acid in Mouse Brain During Ischemia and Electroconvulsive Shock

Cited by 102 publications

References 22 publications

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Ginkgolide B Reduces the Degradation of Membrane Phospholipids to Prevent Ischemia/Reperfusion Myocardial Injury in Rats

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