Prostaglandin E₂ (PGE₂) plays pivotal roles in controlling microglial activation with the EP₂ receptor, a PGE₂ receptor subtype. Activated microglia are often reported to increase cyclooxygenase (COX)-2 expression, followed by PGE₂ production, but it is unclear whether extracellular PGE₂ is involved in microglial PGE₂ synthesis. In the present study, we report that PGE₂ increases COX-2 protein in microglia. In a culture system, PGE₂ at 10^-6 M for 3 h increased COX-2 and microsomal PGE synthase (mPGES)-1 mRNA levels, and reduced mPGES-2, but did not affect COX-1 or cytosolic PGE synthase (cPGES) in microglia. PGE₂ at 10^-6 M for 3 h also increased the COX-2 protein level, but did not affect COX-1, mPGES-1, mPGES-2, or cPGES. An EP₂ agonist, ONO-AE1-259-01, also increased COX-2 and mPGES-1 mRNA levels, and reduced mPGES-2, but did not affect COX-1 or cPGES, whereas an EP₁ agonist, ONO-DI-004, an EP₃ agonist, ONO-AE-248, and an EP₄ agonist, ONO-AE1-329, had no effect. Similar to PGE₂, ONO-AE1-259-01 increased the COX-2 protein level, but did not affect COX-1, mPGES-1, mPGES-2, or cPGES. In addition, the effects of PGE₂ were inhibited by an EP₂ antagonist, PF-04418948, but not by an EP₁ antagonist, ONO-8713, an EP₃ antagonist, ONO-AE3-240, or an EP₄ antagonist, ONO-AE3-208, at 10^-6 M. On the other hand, lipopolysaccharide (LPS) increased PGE₂ production, but the LPS-induced PGE₂ production was not affected by ONO-8713, PF-04418948, ONO-AE3-240, or ONO-AE3-208. These results indicate that PGE₂ increases COX-2 protein in microglia through the EP₂ receptor supporting the idea that extracellular PGE₂ has a triggering aspect for microglial activation.

2018-01-01·International journal of physiology, pathophysiology and pharmacology

Systemic delivery of selective EP1 and EP3 receptor antagonists attenuates pentylenetetrazole-induced seizures in mice.

Article

作者: Oliveira, Mauro S ; Marafiga, Joseane R ; Jesse, Ana C ; Masson, Cíntia J ; Mello, Carlos F ; Poersch, Alice B ; Henshall, David C ; Lenz, Quéli F ; Reschke, Cristina R

Neuroinflammation plays a major role in brain excitability and may contribute to the development of epilepsy. Prostaglandin E₂ (PGE₂) is a direct mediator of inflammatory responses and, through EP receptors, plays an important role in neuronal excitability. Pharmacological evidence supports that centrally-administered EP1 and EP3 receptor antagonists reduced acutely evoked seizures in rats. Translation of these findings would benefit from evidence of efficacy with a more clinically relevant route of delivery and validation in another species. In the current study we investigated whether the systemic administration of EP1 and EP3 agonists and antagonists modulate pentylenetetrazole (PTZ)-induced seizures in mice. In addition, it was examined whether these compounds alter Na⁺, K⁺-ATPase activity, an enzyme responsible for the homeostatic ionic equilibrium and, consequently, for the resting membrane potential in neurons. While the systemic administration of EP1 and EP3 antagonists (ONO-8713 and ONO-AE3-240, respectively) attenuated, the respective agonists (ONO-DI-004 and ONO-AE-248) potentiated PTZ-induced seizures (all compounds injected at the dose of 10 µg/kg, s.c., 30 min before PTZ challenge). Co-administration of either EP1 or EP3 agonist with the respective antagonists nullified the anticonvulsant effects of EP1/3 receptor blockade. In addition, EP1 and EP3 agonists exacerbated PTZ-induced decrease of Na⁺, K⁺-ATPase activity in both cerebral cortex and hippocampus, whereas, EP1 and EP3 antagonists prevented PTZ-induced decrease of Na⁺, K⁺-ATPase activity in both structures. Our findings support and extend evidence that EP1 and EP3 receptors may be novel targets for the development of anticonvulsant drugs.

2014-10-01·Biomedicine & Pharmacotherapy2区 · 医学

Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus

2区 · 医学

Article

作者: Hosono, Kanako ; Majima, Masataka ; Ito, Yoshiya ; Okizaki, Shin-Ichiro ; Shichiri, Masayoshi ; Oba, Kazuhito ; Amano, Hideki

Vascular complications such as foot ulcers are a hallmark of diabetes mellitus (DM), although the molecular mechanisms that underlie vascular dysfunction remain unclear. Herein, we show that angiogenesis, which is indispensable to the healing of ulcers, is suppressed in polyurethane sponge implants in mice with DM and reduced proangiogenic signaling. DM was induced in male C57BL/6 mice by intraperitoneal injection of streptozotocin (100mg/kg). Polyurethane sponge disks were implanted into subcutaneous tissues on the backs of mice, and angiogenesis and expression of related factors were analyzed in sponge granulation tissues. Densities of platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive vascular structures and PECAM-1 expression in sponge granulation tissues were increased over time in control mice and reduced in diabetic mice. The reductions in diabetic mice were accompanied by reduced expression of inducible cyclo-oxygenase-2 and microsomal prostaglandin E synthase-1. The prostaglandin E receptor subtype EP3 was downregulated in sponge granulation tissues in diabetic mice, whereas EP1, EP2, and EP4 were not. The expression of the proangiogenic growth factor vascular endothelial growth factor (VEGF)-A and the chemokine stromal cell-derived factor-1 (SDF-1) were both reduced in diabetic mice. Treatment of diabetic mice with a selective agonist of EP3, ONO-AE 248 (30 nmol/site/day, topical injection), reversed suppression of angiogenesis in diabetic mice. These results indicate that proangiogenic EP3 signaling is suppressed in diabetic mice with reduced expression of VEGF and SDF-1. Stimulation of EP3 signaling restored angiogenesis in a sponge implant model in mice with DM. This suggests that topical application of an EP3 agonist could be a novel strategy to treat foot ulcers in patients with DM.

100 项与 ONO-AE-248 相关的药物交易

登录后查看更多信息