最新论文
更多信息
[已阅读317次]
神经药理及新药发现课题组徐江平教授在Journal of Pharmacology and Experimental Therapeutics上发表研究论文
近日,神经药理及新药发现徐江平教授课题组在Journal of Pharmacology and Experimental Therapeutics(JPET)上发表了题为“Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition”的研究论文。 2017年初,徐江平教授研究团队在ACS Chemical Neurosci (ACS Chem Neurosci. 2017, 8(1):135-146.)杂志上报道了自主合成的N-烷基邻苯二酰胺类化合物的抗炎作用,并证实了这类化合物具有显著的抑制PDE4酶活性的作用(IC50=47 nM)。本研究是对上一类化合物抗神经炎症作用及作用信号通路的进一步探索。研究团队通过建立脂多糖(LPS)诱导的动物体内炎症模型及小胶质细胞体外炎症模型,发现选择性PDE4抑制剂FCPR03在体内、体外炎症模型中均可显著抑制TNF-α, IL-1β 及IL-6的产生。对这一现象的机制研究发现FCPR03可显著增加神经细胞内cAMP的含量,从激活PKA/CREB信号通路。同时发现FCPR03不影响小胶质细胞内NF-κB p65的蛋白表达,但可促进NF-κB p65自细胞核内转位至细胞浆内,而PKA抑制剂则可以阻断FCPR03对炎症因子产生的抑制作用。这一现象综合起来,体现在行为学上表现为模型动物摄食量的增加及认知功能的改善。 JPET由美国药理与实验治疗学会于1909年创刊,已有100多年的历史,是药理学和实验治疗学领域的老牌经典杂志,在行业内具有较高的影响力。该杂志在中科院JCR分区下为大类医学2区,Top级杂志;小类为药学2区杂志(IF=3.76)。 此论文受到国家自然科学基金面上项目、国家自然科学基金青年基金、新药创制重大专项及广东省科技计划等基金资助。2014级硕士研究生邹征强为本论文的第一作者,徐江平教授为该论文的通讯作者。 Zheng-Qiang Zou, Jia-Jia Chen, Hong-Fang Feng, Yu-Fang Cheng, Hai-Tao Wang, Zhong-Zhen Zhou, Hai-Biao Guo, Wenhua Zheng and Jiang-Ping Xu. Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition. J Pharmacol Exp Ther. 2017 Apr 27. pii: jpet.116.239608. doi: 10.1124/jpet.116.239608. [Epub ahead of print] Abstract Over activation of microglia contributes to the induction of neuroinflammation, which is highly involved in the pathology of many neurodegenerative diseases. Phosphodiesterase 4 (PDE4) represents a promising therapeutic target for anti-inflammation. However, the dose-limiting side effects, such as nausea and emesis, have impeded their clinic application. FCPR03, a novel selective PDE4 inhibitor synthesized in our laboratory, shows little or no emetic potency. However, the anti-inflammatory activities of FCPR03 in vitro and in vivo and the molecular mechanisms are still not clearly understood. This study was undertaken to delineate the anti-inflammatory effect of FCPR03 both in vitro and in vivo and try to explore whether those effects were regulated by PDE4-mediated signaling pathway. BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and mice intraperitoneally injected by LPS were established as in vitro and in vivo models of inflammation. Our results showed that FCPR03 dose-dependently suppressed the production of TNF-α, IL-1β and IL-6 in BV-2 microglial cells treated with LPS. Interestingly, the role of FCPR03 on the production of pro-inflammatory factors was reversed by pretreatment with Protein kinase A (PKA) inhibitor H89. In addition, FCPR03 reduced the levels of pro-inflammatory factors in the hippocampus and cortex of mice injected with LPS. Our results further demonstrated FCPR03 effectively increased production of cAMP, promoted cAMP response element binding protein (CREB) phosphorylation and inhibited nuclear factor kappa B (NF-κB) activation both in vitro and in vivo. Our findings suggest that FCPR03 inhibits the neuroinflammatory response through the activation of cAMP/PKA/CREB signaling pathway and NF-κB inhibition.