Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice

Yan Ying Fan, Wei Wei Hu, Hai Bin Dai, Jian Xiang Zhang, Lu Yi Zhang, Ping He, Yao Shen, Hiroshi Ohtsu, Er Qing Wei, Zhong Chen

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)


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% O2) 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.

Original languageEnglish
Pages (from-to)305-314
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number1
Publication statusPublished - 2011 Jan


  • histamine
  • hypoxic preconditioning
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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