Pharmacology of ABT-491, a highly potent platelet-activating factor receptor antagonist

Albert, Daniel H.; Magoc, Terrance J.; Tapang, Paul; Luo, Gongjin; Morgan, Douglas W.; Curtin, Michael L.; Sheppard, George S.; Xu, Lianhong; Heyman, H. Robin; Davidsen, Steven K.; Summers, James Bradley; Carter, George W.

doi:10.1016/s0014-2999(97)00109-x

Cited by 28 publications

(28 citation statements)

References 38 publications

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“…4C). The inhibition was achieved at inhibitor doses commonly used by others (44,45). In summary, Pam3CSK4 stimulates RAW 264.7 cells to produce NO just as LTA does.…”

Section: A Synthetic Lipopeptide Pam3csk4 Induces No Production Jusmentioning

confidence: 93%

“…To investigate the role of PAFR in this lipopeptide-induced NO production, RAW 264.7 cells were stimulated with Pam3CSK4 in the presence of one of two PAFR antagonists (CV6209 or ABT-491). ABT-491 was tested because it is not a PAF analog like CV6209 and its inhibition mechanism is different from CV6209 (44,45). Production of NO, but not of TNF-␣, was significantly reduced in the presence of CV6209 (Fig.…”

Section: A Synthetic Lipopeptide Pam3csk4 Induces No Production Jusmentioning

confidence: 99%

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Lipoteichoic Acid-Induced Nitric Oxide Production Depends on the Activation of Platelet-Activating Factor Receptor and Jak2

Han

Kim

Seo

et al. 2006

The Journal of Immunology

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NO production by macrophages in response to lipoteichoic acid (LTA) and a synthetic lipopeptide (Pam3CSK4) was investigated. LTA and Pam3CSK4 induced the production of both TNF-α and NO. Inhibitors of platelet-activating factor receptor (PAFR) blocked LTA- or Pam3CSK4-induced production of NO but not TNF-α. Jak2 tyrosine kinase inhibition blocked LTA-induced production of NO but not TNF-α. PAFR inhibition blocked phosphorylation of Jak2 and STAT1, a key factor for expressing inducible NO synthase. In addition, LTA did not induce IFN-β expression, and p38 mitogen-activated protein serine kinase was necessary for LTA-induced NO production but not for TNF-α production. These findings suggest that Gram-positive bacteria induce NO production using a PAFR signaling pathway to activate STAT1 via Jak2. This PAFR/Jak2/STAT1 signaling pathway resembles the IFN-β, type I IFNR/Jak/STAT1 pathway described for LPS. Consequently, Gram-positive and Gram-negative bacteria appear to have different but analogous mechanisms for NO production.

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“…4C). The inhibition was achieved at inhibitor doses commonly used by others (44,45). In summary, Pam3CSK4 stimulates RAW 264.7 cells to produce NO just as LTA does.…”

Section: A Synthetic Lipopeptide Pam3csk4 Induces No Production Jusmentioning

confidence: 93%

Section: A Synthetic Lipopeptide Pam3csk4 Induces No Production Jusmentioning

confidence: 99%

Lipoteichoic Acid-Induced Nitric Oxide Production Depends on the Activation of Platelet-Activating Factor Receptor and Jak2

Han

Kim

Seo

et al. 2006

The Journal of Immunology

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“…To inhibit CXCR2-mediated chemotaxis, we used SB225002 (36,37). Furthermore, ABT-491 was used to block PAFR-mediated chemotaxis (38,39). The CXCR2 inhibitor SB225002 reduced chemotaxis of WT neutrophils to the same extent as the lack of TRPC6 channels ( Fig.…”

Section: Intermediary Chemotaxis Depends On Trpc6 Channelsmentioning

confidence: 96%

TRPC6 Regulates CXCR2-Mediated Chemotaxis of Murine Neutrophils

Lindemann

Umlauf

Frank

et al. 2013

The Journal of Immunology

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Unraveling the mechanisms involved in chemotactic navigation of immune cells is of particular interest for the development of new immunoregulatory therapies. It is generally agreed upon that members of the classical transient receptor potential channel family (TRPC) are involved in chemotaxis. However, the regulatory role of TRPC channels in chemoattractant receptor-mediated signaling has not yet been clarified in detail. In this study, we demonstrate that the TRPC6 channels play a pronounced role in CXCR2-mediated intermediary chemotaxis, whereas N-formyl-methionine-leucine-phenylalanine receptor–mediated end-target chemotaxis is TRPC6 independent. The knockout of TRPC6 channels in murine neutrophils led to a strongly impaired intermediary chemotaxis after CXCR2 activation which is not further reinforced by CXCR2, PI3K, or p38 MAPK inhibition. Furthermore, CXCR2-mediated Ca2+ influx but not Ca2+ store release was attenuated in TRPC6−/− neutrophils. We demonstrate that the TRPC6 deficiency affected phosphorylation of AKT and MAPK downstream of CXCR2 receptor activation and led to altered remodeling of actin. The relevance of this TRPC6-depending defect in neutrophil chemotaxis is underscored by our in vivo findings. A nonseptic peritoneal inflammation revealed an attenuated recruitment of neutrophils in the peritoneal cavity of TRPC6−/− mice. In summary, this paper defines a specific role of TRPC6 channels in CXCR2-induced intermediary chemotaxis. In particular, TRPC6-mediated supply of calcium appears to be critical for activation of downstream signaling components.

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“…hidroklorid) çok güçlü bir PAF almaç antagonistidir (16). Literatürde ABT-491'in H‹BH'de anti-apopitotik etki gösterdi¤ini ortaya koyan sadece bir çal›flma vard›r (17).…”

Section: Giriflunclassified

Hipoksik iskemik beyin hasarı oluşturulan yenidoğan sıçanlarda ABT-491 uygulamasının görsel uyarılma potansiyelleri üzerine etkileri

Atıcı¹

2010

tpa

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H Hi ip po ok ks si ik k i is sk ke em mi ik k b be ey yi in n h ha as sa ar r› › o ol lu ufl flt tu ur ru ul la an n y ye en ni id do o¤ ¤a an n s s› ›ç ça an nl la ar rd da a A AB BT T--4 49 91 1 u uy yg gu ul la am ma as s› ›n n› ›n n g gö ör rs se el l u uy ya ar r› ›l lm ma a p po ot ta an ns si iy ye el ll le er ri i ü üz ze er ri in ne e e et tk ki il le er ri i T Th he e e ef ff fe ec ct ts s o of f A AB BT T--4 49 91 1 a ad dm mi in ni is st tr ra at ti io on n o on n v vi is su ua al l e ev vo ok ke ed d p po ot te en nt ti ia al ls s i in n r ra at t m mo od de el l o of f h hy yp po ox xi ic c i is sc ch he em mi ic c b br ra ai in n i in nj ju ur ry y S Su um mm ma ar ry yAim: In the present study, we aimed to investigate the effects of ABT-491 on visual evoked potentials (VEP) in rat model of hypoxic ischemic brain injury (HIBI). Material and Method:Fifty-seven male Wistar newborn rats were used in this study. Animals were divided into three groups randomly. HIBI was formed on postnatal seventh day according to modified Levine-Rice model in 1st (n=18) and 2nd (n=20) groups. Third group (n=19) served as sham group. After HIBI, ABT-491 was applied intraperitoneally to rats in the 1st group (ABT group) and saline was administered to the rats in the 2nd group (saline group). On postnatal 16th weeks, VEPs were recorded from Ag-AgCl disc electrode placed on the occipital region. Results:The latencies of P3 wave were shorter in the ABT group than the saline group (p<0.05). Peak-to-peak amplitudes of P2-N2 and N2-P3 were smaller in the ABT and saline groups compared to the sham group (for all pairwise comparisons p<0.001).Conclusions:It was concluded that HIBI caused a decrement in amplitudes of VEP responses and this change could not be ameliorated with ABT-491. However, shortening in latencies of P3 wave could be ameliorated with ABT-491 treatment after HIBI was formed. (Turk Arch Ped 2010; 45: 319-23)

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Pharmacology of ABT-491, a highly potent platelet-activating factor receptor antagonist

Cited by 28 publications

References 38 publications

Lipoteichoic Acid-Induced Nitric Oxide Production Depends on the Activation of Platelet-Activating Factor Receptor and Jak2

Lipoteichoic Acid-Induced Nitric Oxide Production Depends on the Activation of Platelet-Activating Factor Receptor and Jak2

TRPC6 Regulates CXCR2-Mediated Chemotaxis of Murine Neutrophils

Hipoksik iskemik beyin hasarı oluşturulan yenidoğan sıçanlarda ABT-491 uygulamasının görsel uyarılma potansiyelleri üzerine etkileri

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