title: A new coumarin derivative, IMM-H004, attenuates okadaic acid-induced spatial memory impairment in rats.
abstract: OBJECTIVE
  A novel coumarin derivative 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin (IMM-H004) has shown anti-apoptotic, anti-inflammatory and neuroprotective activities. In this study we investigated the effects of IMM-H004 on spatial memory in rats treated with okadaic acid (OKA), which was used to imitate Alzheimer's disease (AD)-like symptoms.
  
  
  METHODS
  SD rats were administered IMM-H004 (8 mg·kg(-1)·d(-1), ig) or donepezil (positive control, 1 mg·kg(-1)·d(-1), ig) for 25 d. On d 8 and 9, OKA (200 ng) was microinjected into the right ventricle. Morris water maze test was used to evaluate the spatial memory impairments. Tau and β-amyloid (Aβ) pathology in the hippocampus was detected using Western blot and immunohistochemistry. TUNEL staining was used to detect cell apoptosis.
  
  
  RESULTS
  OKA-treated rats showed significant impairments of spatial memory in Morris water maze test, which were largely reversed by administration of IMM-H004 or donepezil. Furthermore, OKA-treated rats exhibited significantly increased phosphorylation of tau, deposits of Aβ protein and cell apoptosis in the hippocampus, which were also reversed by administration of IMM-H004 or donepezil.
  
  
  CONCLUSIONS
  Administration of IMM-H004 or donepezil protects rats against OKA-induced spatial memory impairments via attenuating tau or Aβ pathology. Thus, IMM-H004 may be developed as a therapeutic agent for the treatment of AD.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiu-yun
authors.initials: XY
authors.lastname: Song
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.|Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Hunan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Shi-feng
authors.initials: SF
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Jin-feng
authors.initials: JF
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Peng-fei
authors.initials: PF
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zuo
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Lian-kun
authors.initials: LK
authors.lastname: Song
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.|Hunan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Nai-hong
authors.initials: NH
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003374:Coumarins / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D019319:Okadaic Acid; D017207:Rats, Sprague-Dawley; D065852:Spatial Memory / Q000187:drug effects*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003374:Coumarins; C588372:IMM-H004; D016875:tau Proteins; D019319:Okadaic Acid
references.citation: Eur J Pharmacol. 2013 Jun 15;710(1-3):29-38
references.pmid: 23588117
references.citation: Neuroscience. 2013 Jul 9;242:28-38
references.pmid: 23523945
references.citation: Eur J Pharmacol. 2014 Jan 15;723:259-66
references.pmid: 24291097
references.citation: Brain Res Bull. 2014 Jul;106:30-8
references.pmid: 24878446
references.citation: Biochem Soc Trans. 2014 Oct;42(5):1286-90
references.pmid: 25233405
references.citation: Mol Neurobiol. 2014 Dec;50(3):852-65
references.pmid: 24710687
references.citation: CNS Neurosci Ther. 2015 Mar;21(3):280-8
references.pmid: 25601434
references.citation: Acta Pharmacol Sin. 2015 Mar;36(3):311-22
references.pmid: 25640478
references.citation: Acta Pharmacol Sin. 2015 May;36(5):553-64
references.pmid: 25891085
references.citation: Neuropharmacology. 2015 Aug;95:29-36
references.pmid: 25744714
references.citation: Neuroscience. 1995 Dec;69(3):691-8
references.pmid: 8596639
references.citation: J Biol Chem. 2000 Feb 25;275(8):5535-44
references.pmid: 10681533
references.citation: J Neurosci Methods. 1980 Dec;3(2):129-49
references.pmid: 6110810
references.citation: J Neurosci. 1997 Aug 1;17(15):5726-37
references.pmid: 9221771
references.citation: Neurobiol Aging. 1998 Jan-Feb;19(1):3-13
references.pmid: 9562497
references.citation: Neuron. 2005 Mar 3;45(5):675-88
references.pmid: 15748844
references.citation: Hippocampus. 2006;16(9):755-64
references.pmid: 16883558
references.citation: Nat Protoc. 2006;1(2):848-58
references.pmid: 17406317
references.citation: J Alzheimers Dis. 2008 Aug;14(4):365-70
references.pmid: 18688085
references.citation: J Alzheimers Dis. 2009;16(1):15-27
references.pmid: 19158417
references.citation: Brain Res. 2010 Jan 14;1309:66-74
references.pmid: 19883632
references.citation: J Neurosci Methods. 2011 May 15;198(1):44-52
references.pmid: 21419797
references.citation: Eur J Neurosci. 2012 Jun;35(11):1705-17
references.pmid: 22594877
references.citation: Biochem Soc Trans. 2012 Aug;40(4):644-52
references.pmid: 22817709
references.citation: Eur J Pharmacol. 2012 Sep 5;690(1-3):90-8
references.pmid: 22749976
references.citation: Arch Neurol. 2012 Jun;69(6):709-13
references.pmid: 22529247
references.citation: Neuroscience. 2013 May 15;238:97-113
references.pmid: 23415789
references.citation: J Neurochem. 2013 Nov;127(4):562-74
references.pmid: 23711227