title: Targeted disruption of organic cation transporter 3 (Oct3) ameliorates ischemic brain damage through modulating histamine and regulatory T cells.
abstract: The organic cation transporters OCT1, 2, and 3 (SLC22A1-3) have been implicated in the elimination of biogenic amines such as histamine. Among them, OCT3 was identified as an uptake-2 transporter, responsible for clearance of histamine. Because increasing evidence suggests the involvement of histamine in cerebral ischemia, we investigated the effects of targeted disruption of organic cation transporter-3 (Oct3) on the severity of ischemic brain damage. Transient focal ischemia for 1 hour was induced by occlusion of the middle cerebral artery (MCA) of homozygous Oct3-deficient mice and their wild-type (Wt) littermates. Although targeted disruption of Oct3 did not affect physiological parameters after MCA occlusion, this disruption significantly increased histamine content in the ischemic cortex and significantly reduced the infarct volume after cerebral ischemia. Furthermore, targeted disruption of Oct3 prevented the reduction of regulatory T-cell proportion after cerebral ischemia while this disruption did not affect Th1 and Th2 cells proportions after ischemia. Since repeated administration of L-histidine (a precursor of histamine) to Wt mice also showed the same effects, our observations suggested that OCT3 is the molecule responsible for clearance of ischemia-induced histamine in the brain and targeted disruption of Oct3 ameliorated ischemic brain damage through an increase in regulatory T cells.
authors: Department of Functional Histology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors: Pengxiang
authors: P
authors: Zhu
authors: Ryuji
authors: R
authors: Hata
authors: Masahito
authors: M
authors: Ogasawara
authors: Fang
authors: F
authors: Cao
authors: Kenji
authors: K
authors: Kameda
authors: Kohei
authors: K
authors: Yamauchi
authors: Alfred H
authors: AH
authors: Schinkel
authors: Kazutaka
authors: K
authors: Maeyama
authors: Masahiro
authors: M
authors: Sakanaka
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D055786:Gene Knockout Techniques; D006632:Histamine / Q000276:immunology*; D006639:Histidine / Q000008:administration & dosage / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008050:Lipid A / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D008050:Lipid A; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D009569:Nitric Oxide; D006639:Histidine; D006632:Histamine