Dzietko M, Derugin N, Wendland M F, Vexler Z S, Ferriero D M
Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
Transl Stroke Res. 2013 Apr;4(2):189-200. doi: 10.1007/s12975-012-0221-6.
Neonatal stroke occurs in one in 4,000 live births and leads to significant morbidity and mortality. Approximately two thirds of the survivors have long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after neonatal stroke are not clearly understood, and preventive measures and treatments are nonexistent in the clinical setting. In this study, we investigated the effect of vascular endothelial growth factor (VEGF) treatment on histological recovery and angiogenic response to the developing brain after an ischemic insult. Ten-day-old Sprague-Dawley rats underwent right middle cerebral arterial occlusion (MCAO) for 1.5 h. Diffusion-weighted MRI during occlusion confirmed focal ischemia that was then followed by reperfusion. On group of animals received 5-bromo-2-deoxyuridine and sacrificed at postnatal day (P)18 or P25. A second group of animals was treated with VEGF (1.5 µg/kg, icv) or phosphate-buffered saline (PBS) at P18 and perfusion fixed at P25. Based on Nissl and iron staining, a single VEGF injection reduced the injury score, compared to the animals that underwent MCAO and PBS injection. Furthermore, neurodegeneration represented by neuronal nuclei staining was markedly diminished. In addition, animals treated with VEGF revealed a positive trend in endothelial proliferation and a significant increase in total vessel volume in the peri-infarct region of the caudate. The number of Iba1-positive microglial cells was significantly reduced after a single VEGF injection, and myelin basic protein expression was enhanced in the caudate after ischemia without an effect of VEGF treatment. In conclusion, delayed treatment with VEGF ameliorates injury, promotes endothelial cell proliferation, and increases total vascular volume following neonatal stroke. These results suggest that VEGF has a neuroprotective effect, in part by enhancing endogenous angiogenesis. These data contribute to a better understanding of neonatal stroke.
新生儿中风在每4000例活产中发生1例，会导致严重的发病和死亡。约三分之二的幸存者有长期后遗症，包括癫痫发作和神经功能缺损。然而，新生儿中风后恢复的病理生理机制尚不清楚，临床环境中也不存在预防措施和治疗方法。在本研究中，我们调查了血管内皮生长因子（VEGF）治疗对缺血性损伤后发育中大脑的组织学恢复和血管生成反应的影响。10日龄的斯普拉格-道利大鼠接受右侧大脑中动脉闭塞（MCAO）1.5小时。闭塞期间的扩散加权MRI证实了局灶性缺血，随后进行再灌注。一组动物接受5-溴-2-脱氧尿苷，并在出生后第（P）18天或P25天处死。第二组动物在P18时用VEGF（1.5μg/kg，脑室内注射）或磷酸盐缓冲盐水（PBS）治疗，并在P25时进行灌注固定。基于尼氏染色和铁染色，与接受MCAO和PBS注射的动物相比，单次注射VEGF降低了损伤评分。此外，以神经元核染色为代表的神经变性明显减轻。此外，用VEGF治疗的动物在内皮细胞增殖方面呈阳性趋势，尾状核梗死周围区域的总血管体积显著增加。单次注射VEGF后，Iba1阳性小胶质细胞数量显著减少，缺血后尾状核中髓鞘碱性蛋白表达增强，但VEGF治疗无此作用。总之，VEGF延迟治疗可改善新生儿中风后的损伤，促进内皮细胞增殖，并增加总血管体积。这些结果表明，VEGF具有神经保护作用，部分是通过增强内源性血管生成实现的。这些数据有助于更好地理解新生儿中风。
