title: Atomoxetine Protects Against NMDA Receptor-mediated Hippocampal Neuronal Death Following Transient Global Cerebral Ischemia.
abstract: Atomoxetine has been widely used for the treatment of attention-deficit/ hyperactivity disorder. ATX has additional abilities such as antagonistic effects on the N-methyl-Daspartate receptors (NMDARs) and benefit effects in some animal models of neurological disorders. However, there were few studies regarding protective effects and related mechanisms of ATX against cerebral ischemic insults.
  
  
  
  The objective of this study is to investigate neuroprotection of ATX pretreatment and its mechanisms in the hippocampal cornu ammonis 1 (CA1) region following transient global cerebral ischemia in gerbils.
  
  
  
  Gerbils were subjected to transient global cerebral ischemia induced by the occlusion of common carotid arteries for 5 min. Thirty mg/kg of ATX was administrated intraperitoneally once daily for 3 days before ischemic surgery. To examine neuroprotective effects of ATX, we carried out neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B histofluorescence staining. In addition, immunoreactivities of NMDAR1, NMDAR2A/B, B-cell lymphoma 2 (Bcl-2) and Bcl-2- associated X protein (Bax) are closely related with neuroexcitotoxicity.
  
  
  
  ATX pretreatment reduced ischemia-induced hyperactivity and protected CA1 pyramidal neurons from ischemia. Pretreatment with ATX significantly attenuated ischemia-induced increases of NMDAR1 and NMDAR2A/B immunoreactivities in the CA1 pyramidal neurons at early time following ischemia. In addition, significant ischemia-induced alterations of Bcl-2 and Bax immunoreactivities were not observed in the ATX-treated group following ischemia.
  
  
  
  These results show that pretreatment with ATX protected against ischemic neuronal via inhibition of ischemia-induced excitotoxicity at early time following transient global cerebral ischemia.
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon 24252. Korea.
authors.forename: Joon Ha
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Surgery, School of Medicine, Kangwon National University, Chuncheon 24341. Korea.
authors.forename: Yang Hee
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon 24252. Korea.
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon 24252. Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Surgery, School of Medicine, Kangwon National University, Chuncheon 24341. Korea.
authors.forename: Seongkweon
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Pediatrics, Dongtan Sacred Heart Hospital, School of Medicine, Hallym University, Hwaseong 18450. Korea.
authors.forename: Sung Koo
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, 24252. Korea.
authors.forename: Il Jun
authors.initials: IJ
authors.lastname: Kang
authors.affiliation: Department of Molecular and Cellular Biochemistry School of Medicine, Kangwon National University, Chuncheon 24341. Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 24341. Korea.
authors.forename: Tae-Kyeong
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 24341. Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 31116. Korea.
authors.forename: Choong-Hyun
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000069445:Atomoxetine Hydrochloride / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects*; D004195:Disease Models, Animal; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016194:Receptors, N-Methyl-D-Aspartate; D051028:bcl-2-Associated X Protein; D000069445:Atomoxetine Hydrochloride; D010751:Phosphopyruvate Hydratase
keywords: CA1 pyramidal neurons; Ischemic insults; delayed neuronal death; neuroexcitotoxicity; neuroprotection; noradrenergic reuptake
  inhibitor