title: Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice.
abstract: We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O(2)) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.
authors.affiliation: Department of Pharmacology, Institute of Neuroscience, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yan-ying
authors.initials: YY
authors.lastname: Fan
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Hu
authors.forename: Hai-bin
authors.initials: HB
authors.lastname: Dai
authors.forename: Jian-xiang
authors.initials: JX
authors.lastname: Zhang
authors.forename: Lu-yi
authors.initials: LY
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Yao
authors.initials: Y
authors.lastname: Shen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Er-qing
authors.initials: EQ
authors.lastname: Wei
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism / Q000502:physiology*; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002534:Hypoxia, Brain / Q000150:complications* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000503:physiopathology; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000209:etiology* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D002934:Cinnamates; C483044:SU 1498; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine; D040301:Vascular Endothelial Growth Factor Receptor-2; D006640:Histidine Decarboxylase