神经药理学报 ›› 2017, Vol. 7 ›› Issue (2): 27-27.

• 阿尔茨海默病相关研究 • 上一篇    下一篇

A Novel Mechanism Underlying the Protective Effect of PDE4 Inhibitor Against Cognitive Impairment:Inhibiting Neuroinflammation through Inducing Autophagy in Microglial Cells

YOU Ting-ting,GUO Hai-biao,WANG Hai-tao,XU Jiang-ping   

  1. Department of Neuropharmacology and Drug Discovery,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,510515,China
  • 出版日期:2017-04-26 发布日期:2017-12-01
  • 作者简介:XU Jiang-ping,E-mail:jpx@smu.edu.cn
  • 基金资助:

    Acknowledgement:This work was supported by National Natural Science Fund of China( No. 81373384,81503043).

  • Online:2017-04-26 Published:2017-12-01

摘要: Background:Inhibition of pho sphodiesterase 4 (PDE4) improves the learning and memory abilities in Alzheimer’s disease animal models. The cognition-enhancing effects of PDE4 inhibition involve reduced inflammatory responses in the brain. However,the underlying mechanisms are ill-understood. cAMP induces autophagy,and defi ciency of autophagy leads to elevated inflammatory factors. In the present study,we aimed to investigate the contribution of autophagy to the anti-inflammatory effect of PDE4 inhibitor ROF. Methods:Acidic vesicles were traced by Lysotracker( LYT) red and acridine orange( AO) staining. Autophagosomes in BV-2 cells was observed by immunofluorescence staining of microtubule-associated protein 1 light chain 3 (LC3). Aβ25-35 or lipopolysaccharide (LPS) with ATP were used to activate microglial cells and infl ammasome. Cytokine levels were measured by ELISA method. The levels of pro-infl ammatory factors and essential proteins involved in the formation of autophagosome were detected by Western blotting. Results:ROF increased the level of LC3-II,while the level of p62 was decreased. Enhanced fl uorescent signals were observed in BV-2 cells treated with ROF by AO and LYT red staining. In addition,immunofl uorescence indicated a signifi cant increase in punctate LC3. Both LPS plus ATP and Aβ25-35 enhanced the conversion of procaspase- 1 to cleaved-caspase-1 and increased the production of mature IL-1β. Interestingly,these effects were blocked by the treatment of ROF. Moreover,ROF decreased the apoptosis of neuronal N2a cells in conditioned media from BV-2 microglia. These effects were reversed by inhibition of microglial autophagy. Treatment with ROF also showed enhanced autophagy in mcie treated with LPS. Conclusions:PDE4 inhibitor ROF inhibits infl ammasome activities and reduces the release of IL-1β by inducing autophagy.

关键词: phosphodiesterase 4, autophagy, infl ammasome, microglia