Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Stroke. 2011 Nov;42(11):3265-70. doi: 10.1161/STROKEAHA.111.618801. Epub 2011 Sep 8.
The purpose of this study was to determine whether neuroprotection is feasible without cerebral blood flow augmentation in experimental permanent middle cerebral artery occlusion.
Rats were subjected to permanent middle cerebral artery occlusion by the suture occlusion method and were treated 1 hour thereafter with a single 5-minute intravenous infusion of the postsynaptic density-95 protein inhibitor Tat-NR2B9c (7.5 mg/kg) or saline (n=8/group). Arterial spin-labeled perfusion-weighted MRI and diffusion weighted MRI were obtained with a 4.7-T Bruker system at 30, 45, 70, 90, 120, 150, and 180 minutes postmiddle cerebral artery occlusion to determine cerebral blood flow and apparent diffusion coefficient maps, respectively. At 24 hours, animals were neurologically scored (0 to 5), euthanized, and the brains stained with 2-3-5-triphenyl tetrazolium chloride to ascertain infarct volumes corrected for edema. Additionally, the effects of Tat-NR2B9c on adenosine 5'-triphosphate levels were measured in vitro in neurons subjected to oxygen-glucose deprivation.
Final infarct volume was decreased by 30.3% in the Tat-NR2B9c-treated animals compared with controls (P=0.028). There was a significant improvement in 24 hours neurological scores in the Tat-NR2B9c group compared with controls, 1.8±0.5 and 2.8±1.0, respectively (P=0.021). Relative to controls, Tat-NR2B9c significantly attenuated diffusion-weighted imaging lesion growth and preserved the diffusion-weighted imaging/perfusion-weighted imaging mismatch (ischemic penumbra) without affecting cerebral blood flow in the ischemic core or penumbra. Tat-NR2B9c treatment of primary neuronal cultures resulted in 26% increase in cell viability and 34% greater adenosine 5'-triphosphate levels after oxygen-glucose deprivation.
Preservation of adenosine 5'-triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a postsynaptic density-95 protein inhibitor.
本研究旨在探讨在实验性永久性大脑中动脉闭塞模型中，不增加脑血流的情况下是否可行神经保护。
大鼠采用缝线阻塞法制作永久性大脑中动脉闭塞模型，于闭塞后 1 小时，经静脉内输注单次 5 分钟的突触后密度蛋白-95 抑制剂 Tat-NR2B9c（7.5mg/kg）或生理盐水（n=8/组）进行治疗。采用 4.7-T Bruker 系统进行动脉自旋标记灌注加权 MRI 和弥散加权 MRI 检查，分别于大脑中动脉闭塞后 30、45、70、90、120、150 和 180 分钟获得脑血流和表观弥散系数图。于 24 小时时，对动物进行神经学评分（0 至 5 分），处死动物，并采用 2,3,5-三苯基氯化四氮唑对大脑进行染色，以确定校正水肿的梗死体积。此外，还在体外氧葡萄糖剥夺的神经元中测量 Tat-NR2B9c 对三磷酸腺苷水平的影响。
与对照组相比，Tat-NR2B9c 治疗组的最终梗死体积减少了 30.3%（P=0.028）。Tat-NR2B9c 组 24 小时神经学评分较对照组显著改善，分别为 1.8±0.5 和 2.8±1.0（P=0.021）。与对照组相比，Tat-NR2B9c 显著减轻弥散加权成像病变进展，并保留弥散加权成像/灌注加权成像不匹配（缺血半暗带），而不影响缺血核心或半暗带的脑血流。Tat-NR2B9c 处理原代神经元培养物后，可使细胞活力增加 26%，氧葡萄糖剥夺后三磷酸腺苷水平增加 34%。
在不增加脑血流的情况下，使用突触后密度蛋白-95 抑制剂，可在体外维持三磷酸腺苷水平并在大鼠永久性大脑中动脉闭塞中实现神经保护。
