Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice
Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice
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中枢组胺能系统的激活参与成年小鼠缺氧诱导的中风耐受性
DOI：
10.1038/jcbfm.2010.94
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发表时间：
2011-01-01
影响因子：
6.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Fan, Yan-ying;Hu, Wei-wei;Chen, Zhong
我们推测，中枢组胺能系统的激活是缺氧预处理诱导的神经保护所必需的。野生型（WT）和组氨酸脱羧酶敲除（HDC-KO）小鼠通过3小时缺氧（8%O-2）预处理，48小时后，进行30分钟的大脑中动脉（MCA）闭塞，随后再灌注24小时。低氧预处理改善了用组胺处理的WT或HDC-KO小鼠的神经功能并减少了梗死体积，但在用α-氟甲基组氨酸（α-FMH，HDC的抑制剂）处理的HDC-KO或WT小鼠中没有。激光多普勒血流仪分析表明，低氧预处理改善大脑中动脉周围的领土在缺血WT小鼠，但在HDC-KO小鼠的脑血流量（CBF）。缺氧2、3、4小时后，WT小鼠皮质组胺含量降低，缺氧3小时后，HDC活性增加。缺氧后血管内皮生长因子（VEGF）mRNA和蛋白表达比HDC-KO或α-FMH处理的WT小鼠增加更大。此外，VEGF受体-2拮抗剂SU 1498阻止缺氧预处理对WT小鼠梗死体积的保护作用，并逆转外周CBF增加。因此，内源性组胺是低氧预适应的重要介质。它可能通过增强缺氧诱导的VEGF表达发挥作用。Journal of Cerebral Blood Flow & Metabolism（2011）31，305-314; doi：10.1038/jcbfm.2010.94; 2010年6月30日在线发表
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