期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 31, 期 1, 页码 305-314出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2010.94
关键词
histamine; hypoxic preconditioning; vascular endothelial growth factor
资金
- National Natural Science Foundation of China [30725047, 30572176, 30600757, 30801392]
- National Basic Research of China 973 Program [2009CB521906]
- Zhejiang Provincial Natural Science Foundation of China [Z207289]
- Youth foundation of the Innovative Scientific Research of Zhejiang University [2009QNA7007]
- Ministry of Education, China [NCET-06-0511]
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 alpha-fluoromethylhistidine (alpha-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 alpha-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. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 305-314; doi:10.1038/jcbfm.2010.94; published online 30 June 2010
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