title: TSPO ligand PK11195 alleviates neuroinflammation and beta-amyloid generation induced by systemic LPS administration.
abstract: Translocator protein 18 kDa (TSPO) is now an attractive drug target for controlling neuroinflammation. Studies applying TSPO ligands to neurodegenerative diseases, especially Alzheimer's disease (AD), were rare. Our study was aimed to evaluate the effect of PK11195, a specific TSPO ligand, in an animal model of neuroinflammation caused by systemic LPS administration. C57/BL6 mice were treated with lipopolysaccharide (LPS, 500 μg/kg, i.p.) three days after PK11195 administration (3mg/kg, i.p.). The drugs were not discontinued until the mice were sacrificed. Cognitive function was assessed by Morris water maze (MWM) seven days after LPS injection. Chronic LPS-injection in mice was characterized by cognitive dysfunction, increased expression of cyclooxygenase (COX)-2 and TSPO, elevated Aβ content with increased expression of β-site APP cleaving enzyme-1 (BACE-1) and insulin-degrading enzyme (IDE) as well as decreased brain progesterone and brain-derived neurophic factor (BDNF) level. PK11195 pretreatment protected cognitive function in LPS-injected animals and normalized the inflammatory proteins. Moreover, PK11195 pre-administration decreased elevated hippocampal Aβx-42 levels and increased brain levels of progesterone, allopregnanolone. However, LPS-induced BDNF decrease was not reversed by PK11195 administration. Our data demonstrated that PK11195 could protect cognitive deficits induced by chronic LPS administration. The underling mechanism may involve alleviated neuroinflammation, increased synthesis of neurosteroid and decreased Aβ accumulation accompanied by down-regulation of BACE-1.
authors: Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, China; Department of Anesthesiology, General Hospital of Beijing Military Command, Beijing 100700, China.
authors: Li
authors: L
authors: Ma
authors: Department of Neurosurgery, Air Force General Hospital of the Chinese People's Liberation Army, Beijing 100142, China.
authors: Hui
authors: H
authors: Zhang
authors: Department of Anesthesiology, Affiliated Hospital of Chengde Mdical University, Chengde 067000, China.
authors: Na
authors: N
authors: Liu
authors: Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, China.
authors: Pei-qi
authors: PQ
authors: Wang
authors: Department of Anesthesiology, General Hospital of Beijing Military Command, Beijing 100700, China.
authors: Wen-zhi
authors: WZ
authors: Guo
authors: Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, China.
authors: Qiang
authors: Q
authors: Fu
authors: Department of Anesthesiology, General Hospital of Beijing Military Command, Beijing 100700, China.
authors: Lin-bo
authors: LB
authors: Jiao
authors: Department of Anesthesiology, General Hospital of Beijing Military Command, Beijing 100700, China.
authors: Ya-qun
authors: YQ
authors: Ma
authors: Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: mi_wd301@126.com.
authors: Wei-Dong
authors: WD
authors: Mi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D019208:Brain-Derived Neurotrophic Factor; C463819:Bzrp protein, mouse; D007546:Isoquinolines; D008070:Lipopolysaccharides; D018079:Receptors, GABA; D011374:Progesterone; D011280:Pregnanolone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C037850:PK 11195
keywords: Cognition; LPS; Neuroinflammation; Neurosteroid; PK11195; TSPO