Nuffield Department of Clinical Medicine, Acute Stroke Programme, University of Oxford, Oxford, UK.
J Cereb Blood Flow Metab. 2011 Jan;31(1):132-43. doi: 10.1038/jcbfm.2010.60. Epub 2010 Apr 21.
Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain (PHD) enzymes that regulate the stability of hypoxia-inducible factor (HIF). We investigated the effect of DMOG on the outcome after permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Before and after pMCAO, rats were treated with 40 mg/kg, 200 mg/kg DMOG, or vehicle, and with 40 mg/kg or vehicle after tMCAO. Serial magnetic resonance imaging (MRI) was performed to assess infarct evolution and regional cerebral blood flow (rCBF). Both doses significantly reduced infarct volumes, but only 40 mg/kg improved the behavior after 24 hours of pMCAO. Animals receiving 40 mg/kg were more likely to maintain rCBF values above 30% from the contralateral hemisphere within 24 hours of pMCAO. DMOG after tMCAO significantly reduced the infarct volumes and improved behavior at 24 hours and 8 days and also improved the rCBF after 24 hours. A consistent and significant upregulation of both mRNA and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was associated with the observed neuroprotection, although this was not consistently related to HIF-1α levels at 24 hours and 8 days. Thus, DMOG afforded neuroprotection both at 24 hours after pMCAO and at 24 hours and 8 days after tMCAO. This effect was associated with an increase of VEGF and eNOS and was mediated by improved rCBF after DMOG treatment.
二甲基草酰甘氨酸（DMOG）是脯氨酰-4-羟化酶结构域（PHD）酶的抑制剂，可调节缺氧诱导因子（HIF）的稳定性。我们研究了 DMOG 对大鼠永久性和短暂性大脑中动脉闭塞（p/tMCAO）后结局的影响。在 pMCAO 前后，大鼠分别用 40mg/kg、200mg/kg DMOG 或载体处理，tMCAO 后用 40mg/kg 或载体处理。进行连续磁共振成像（MRI）以评估梗塞演变和局部脑血流（rCBF）。两种剂量均显著降低梗塞体积，但只有 40mg/kg 改善了 pMCAO 后 24 小时的行为。接受 40mg/kg DMOG 的动物在 pMCAO 后 24 小时内更有可能维持 rCBF 值高于对侧半球的 30%。tMCAO 后给予 DMOG 可显著降低梗塞体积，改善 24 小时和 8 天时的行为，并改善 24 小时时的 rCBF。血管内皮生长因子（VEGF）和内皮型一氧化氮合酶（eNOS）的 mRNA 和蛋白水平均持续显著上调与观察到的神经保护有关，尽管这在 24 小时和 8 天时与 HIF-1α水平不一致。因此，DMOG 在 pMCAO 后 24 小时和 tMCAO 后 24 小时和 8 天都提供了神经保护。这种作用与 VEGF 和 eNOS 的增加有关，并通过 DMOG 治疗后 rCBF 的改善来介导。
