Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Anesthesiology. 2011 Feb;114(2):340-54. doi: 10.1097/ALN.0b013e318206ff6f.
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-1α (HIF-1α) 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-1α expression.
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-1α in the neuroprotective effects of orexin-A, the HIF-1α 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.
Orexin-A significantly ameliorated neurologic deficit scores and reduced infarct volume after cerebral ischemia reperfusion. Administration of 30 μg/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-1α expression after cerebral ischemia reperfusion. Moreover, the facilitation of HIF-1α expression was accompanied with inhibition of von Hippel-Lindau expression. Administration of HIF-1α inhibitor suppressed the increase of HIF-1α and reversed the neuroprotective effects of orexin-A.
Orexin-A has a neuroprotective effect against cerebral ischemia-reperfusion injury. These effects may be mediated through the HIF-1α pathway.
最近的研究表明，新型神经肽食欲素-A 在神经元损伤中可能发挥重要作用。然而，食欲素-A 在脑缺血中的作用尚不清楚。最近，研究表明缺氧诱导因子-1α（HIF-1α）可被食欲素-A 激活。本研究旨在验证以下假设：给予外源性食欲素-A 可通过促进 HIF-1α 的表达来减轻缺血再灌注损伤。
Sprague-Dawley 大鼠进行 120 分钟短暂性大脑中动脉闭塞。在缺血前和再灌注开始时，大鼠给予不同剂量的食欲素-A 或载体。为了研究 HIF-1α 在食欲素-A 神经保护作用中的作用，单独或联合使用 HIF-1α 抑制剂 YC-1。评估神经功能缺损评分和梗死体积。采集大脑进行免疫组织化学染色和 Western blot 分析。
食欲素-A 可显著改善缺血再灌注后的神经功能缺损评分和减少梗死体积。给予 30μg/kg 食欲素-A 显示出最佳的神经保护作用。这种作用在再灌注后 7 天仍然存在。此外，食欲素-A 可减少缺血再灌注后细胞凋亡的数量，并显著增强 HIF-1α 的表达。此外，HIF-1α 表达的促进伴随着 von Hippel-Lindau 表达的抑制。给予 HIF-1α 抑制剂抑制了 HIF-1α 的增加，并逆转了食欲素-A 的神经保护作用。
食欲素-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-1α 途径介导。
