Neuroprotective Effect of Orexin-A Is Mediated by an Increase of Hypoxia-inducible Factor-1 Activity in Rat
Neuroprotective Effect of Orexin-A Is Mediated by an Increase of Hypoxia-inducible Factor-1 Activity in Rat
复制标题
大鼠缺氧诱导因子 1 活性增加介导 Orexin-A 的神经保护作用
DOI：
10.1097/aln.0b013e318206ff6f
复制
发表时间：
2011-02-01
期刊：
影响因子：
8.8
通讯作者：
Xiong, Lize
中科院分区：
文献类型：
--
作者：
Yuan, Li-bang;Dong, Hai-long;Xiong, Lize
背景：最近的研究表明，新的神经肽orexin-A可能在神经元损伤中发挥重要作用。然而，食欲素-A在脑缺血中的功能尚不清楚。最近，缺氧诱导因子-1 α（HIF-1 α）被证明是由食欲素-A激活。本研究的目的是检验这一假设，即外源性orexin-A可以减轻缺血再灌注损伤通过促进HIF-1 α expression.Methods：Sprague-Dawley大鼠进行短暂的大脑中动脉闭塞120分钟。大鼠进行了治疗与不同剂量的orexin-A或车辆缺血前和再灌注的发病。为了研究HIF-1 α在食欲素-A的神经保护作用中的作用，单独使用HIF-1 α抑制剂YC-1或与食欲素-A组合使用。评估神经功能缺损评分和梗死体积。结果：Orexin-A能显著改善脑缺血再灌注后神经功能缺损评分，缩小脑梗死体积。施用30 μ g/kg食欲素-A显示出最佳的神经保护作用。再灌注7天后，这种效应仍然存在。此外，食欲素-A减少脑缺血再灌注后凋亡细胞的数量，并显着增强HIF-1 α的表达。此外，HIF-1 α表达的促进伴随着von Hippel-Lindau表达的抑制。结论：Orexin-A对脑缺血再灌注损伤具有神经保护作用。这些作用可能通过HIF-1 α途径介导。
Background: Recent studies suggest that the novel neuropeptide orexin-A may play an essential role during neuronal damage. However, the function of orexin-A during brain ischemia remains unclear. Recently, hypoxia-inducible factor-1 alpha (HIF-1 alpha) was shown to be activated by orexin-A. The aim of the current study is to test the hypothesis that administration of exogenous orexin-A can attenuate ischemia-reperfusion injury through the facilitation of HIF-1 alpha expression.Methods: Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 120 min. Rats were treated with different doses of orexin-A or vehicle before the ischemia and at the onset of reperfusion. To investigate the action of HIF-1 alpha in the neuroprotective effects of orexin-A, the HIF-1 alpha inhibitor YC-1 was used alone or combined with orexin-A. Neurologic deficit scores and infarct volume were assessed. Brains were harvested for immunohistochemical staining and western blot analysis.Results: Orexin-A significantly ameliorated neurologic deficit scores and reduced infarct volume after cerebral ischemia reperfusion. Administration of 30 mu g/kg orexin-A showed optimal neuroprotective effects. This effect was still present 7 days after reperfusion. Furthermore, orexin-A decreased the number of apoptotic cells and significantly enhanced HIF-1 alpha expression after cerebral ischemia reperfusion. Moreover, the facilitation of HIF-1 alpha expression was accompanied with inhibition of von Hippel-Lindau expression. Administration of HIF-1 alpha inhibitor suppressed the increase of HIF-1 alpha and reversed the neuroprotective effects of orexin-A.Conclusions: Orexin-A has a neuroprotective effect against cerebral ischemia-reperfusion injury. These effects may be mediated through the HIF-1 alpha pathway.