Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells

Journal of Neuroinflammation

Mario van der Stelt¹  Thomas Hurrle²  Florian Mohr²  Nicole Volz²  Stefan Bräse²  Soraya Wilke Saliba³  Hannah Jauch³  Albrecht Keil³  Brahim Gargouri³  Bernd L. Fiebich³ 

[1] Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University;Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT);Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg;

关键词: GPR55;    Prostaglandin E2;    Cyclooxygenase;    Microglia;    Neuroinflammation;   

DOI  :  10.1186/s12974-018-1362-7

来源: DOAJ

【 摘 要 】

Abstract Background Neuroinflammation plays a vital role in Alzheimer’s disease and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system, and they play essential roles in the maintenance of homeostasis and responses to neuroinflammation. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia. However, its effects on neuroinflammation, mainly on the production of members of the arachidonic acid pathway in activated microglia, have not been elucidated in detail. Methods In this present study, a series of coumarin derivatives, that exhibit GPR55 antagonism properties, were designed. The effects of these compounds on members of the arachidonic acid cascade were studied in lipopolysaccharide (LPS)-treated primary rat microglia using Western blot, qPCR, and ELISA. Results We demonstrate here that the various compounds with GPR55 antagonistic activities significantly inhibited the release of PGE2 in primary microglia. The inhibition of LPS-induced PGE2 release by the most potent candidate KIT 17 was partially dependent on reduced protein synthesis of mPGES-1 and COX-2. KIT 17 did not affect any key enzyme involved on the endocannabinoid system. We furthermore show that microglia expressed GPR55 and that a synthetic antagonist of the GPR receptor (ML193) demonstrated the same effect of the KIT 17 on the inhibition of PGE2. Conclusions Our results suggest that KIT 17 is acting as an inverse agonist on GPR55 independent of the endocannabinoid system. Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer’s disease, Parkinson, and multiple sclerosis (MS).

【 授权许可】

Unknown