Rocepafant

We previously reported that vascular endothelial growth factor (VEGF) increases vascular permeability through the synthesis of endothelial platelet‐activating factor (PAF), while others reported the contribution of nitric oxide (NO). Herein, we addressed the contribution of VEGF receptors and the role played by PAF and NO in VEGF‐induced plasma protein extravasation. Using a modified Miles assay, intradermal injection in mice ears of VEGF‐A165, VEGF‐A121, and VEGF‐C (1 µM) which activate VEGFR‐2 (Flk‐1) receptor increased vascular permeability, whereas a treatment with VEGFR‐1 (Flt‐1) analogs; PlGF and VEGF‐B (1 µM) had no such effect. Pretreatment of mice with PAF receptor antagonist (LAU8080) or endothelial nitric oxide synthase (eNOS) inhibitor (L‐NAME) abrogated protein extravasation mediated by VEGF‐A165. As opposed to PAF (0.01‐1 µM), treatment with acetylcholine (ACh; up to 100 µM; inducer of NO synthesis) or sodium nitroprusside (SNP; up to 1 µM; NO donor) did not induce protein leakage. Simultaneous pretreatment of mice with eNOS and protein kinase A (PKA) inhibitors restored VEGF‐A165 vascular hyperpermeability suggesting that endogenous NO synthesis leads to PKA inhibition, which support maintenance of vascular integrity. Our data demonstrate that VEGF analogs increase vascular permeability through VEGFR‐2 activation, and that both endogenous PAF and NO synthesis contribute to VEGF‐A165‐mediated vascular permeability. However, PAF but not NO directly increases vascular permeability per se, thereby, suggesting that PAF is a direct inflammatory mediator, whereas NO serves as a cofactor in VEGF‐A165 proinflammatory activities. J. Cell. Biochem. 100: 727–737, 2007. © 2006 Wiley‐Liss, Inc.

Evidence suggests that platelet-activating factor (PAF) is a mediator in inflammatory-based pain. Using the biphasic formalin model in rats, we recently demonstrated that PAF antagonists which were selective for either intracellular or plasma membrane PAF receptors decreased the late-phase of the nociceptive response. Inasmuch as both of the PAF antagonists previously used were administered systemically, and reportedly are able to cross the blood-brain barrier, the anatomic locations at which PAF affects pain processing remained to be elucidated. Since PAF is required for hippocampal-dependent memory consolidation, and since the hippocampus has been shown to mediate the late-phase of formalin-induced nociception, the present study investigated the effects on nociception of administration of PAF antagonists within the hippocampus, and of using agents specific for either plasma membrane (BN 52021) or intracellular (BN 50730) PAF binding sites. Intrahippocampal injections of BN 52021 decreased the late-phase of the nociceptive response in a concentration-dependent manner. In contrast, intrahippocampal administration of BN 50730 had no effect on inflammatory nociception. These findings suggest that hippocampal plasma membrane PAF receptors, but not intracellular PAF binding sites, mediate tonic inflammatory pain processing in rats.