title: Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKβ-dependent AMPK activation.
abstract: Brain inflammation plays an important role in the pathophysiology of many psychiatric and neurological diseases. During brain inflammation, microglia cells are activated, producing neurotoxic molecules and neurotrophic factors depending on their pro-inflammatory M1 and anti-inflammatory M2 phenotypes. It has been demonstrated that Angiotensin II type 1 receptor blockers (ARBs) ameliorate brain inflammation and reduce M1 microglia activation. The ARB telmisartan suppresses glutamate-induced upregulation of inflammatory genes in cultured primary neurons. We wished to clarify whether telmisartan, in addition, prevents microglia activation through polarization to an anti-inflammatory M2 phenotype. We found that telmisartan promoted M2 polarization and reduced M1 polarization in LPS-stimulated BV2 and primary microglia cells, effects partially dependent on PPARγ activation. The promoting effects of telmisartan on M2 polarization, were attenuated by an AMP-activated protein kinase (AMPK) inhibitor or AMPK knockdown, indicating that AMPK activation participates on telmisartan effects. Moreover, in LPS-stimulated BV2 cells, telmisartan enhancement of M2 gene expression was prevented by the inhibitor STO-609 and siRNA of calmodulin-dependent protein kinase kinase β (CaMKKβ), an upstream kinase of AMPK. Furthermore, telmisartan enhanced brain AMPK activation and M2 gene expression in a mouse model of LPS-induced neuroinflammation. In addition, telmisartan reduced the LPS-induced sickness behavior in this in vivo model, and this effect was prevented by prior administration of an AMPK inhibitor. Our results indicate that telmisartan can be considered as a novel AMPK activator, suppressing microglia activation by promoting M2 polarization. Telmisartan may provide a novel, safe therapeutic approach to treat brain disorders associated with enhanced inflammation.
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Road, Shanghai 201203, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lyzhang@cpu.edu.cn.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: tpang@cpu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001565:Benzoates / Q000008:administration & dosage*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D016764:Cell Polarity / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D055809:Illness Behavior / Q000187:drug effects; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D008070:Lipopolysaccharides; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D000077333:Telmisartan
keywords: AMP-activated protein kinase; Microglia polarization; Neuroinflammation; Telmisartan