Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
J Neuroinflammation. 2018 Nov 19;15(1):322. doi: 10.1186/s12974-018-1362-7.
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.
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.
We demonstrate here that the various compounds with GPR55 antagonistic activities significantly inhibited the release of PGE in primary microglia. The inhibition of LPS-induced PGE 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 PGE.
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).
神经炎症在阿尔茨海默病和其他神经退行性疾病中起着至关重要的作用。小胶质细胞是中枢神经系统的固有单核免疫细胞，它们在维持内环境平衡和对神经炎症的反应中发挥着重要作用。孤儿 G 蛋白偶联受体 55（GPR55）已被报道可调节炎症，并在单核细胞和小胶质细胞等免疫细胞中表达。然而，其对神经炎症的影响，主要是对激活的小胶质细胞中花生四烯酸途径成员的产生，尚未详细阐明。
在本研究中，设计了一系列表现出 GPR55 拮抗特性的香豆素衍生物。使用 Western blot、qPCR 和 ELISA 研究了这些化合物在脂多糖（LPS）处理的原代大鼠小胶质细胞中对花生四烯酸级联成员的影响。
我们在这里证明，具有 GPR55 拮抗活性的各种化合物可显著抑制原代小胶质细胞中 PGE 的释放。最有效的候选物 KIT 17 对 LPS 诱导的 PGE 释放的抑制作用部分依赖于 mPGES-1 和 COX-2 蛋白合成的减少。KIT 17 不影响内源性大麻素系统中涉及的任何关键酶。我们还表明，小胶质细胞表达 GPR55，并且 GPR 受体的合成拮抗剂（ML193）证明了 KIT 17 对 PGE 抑制的相同作用。
我们的结果表明，KIT 17 作为 GPR55 的反向激动剂起作用，与内源性大麻素系统无关。靶向 GPR55 可能是治疗具有神经炎症背景的神经退行性疾病（如阿尔茨海默病、帕金森病和多发性硬化症）的新治疗选择。
