Sildenafil Mediates Blood-Flow Redistribution and Neuroprotection After Neonatal Hypoxia-Ischemia
Sildenafil Mediates Blood-Flow Redistribution and Neuroprotection After Neonatal Hypoxia-Ischemia
复制标题
DOI：
10.1161/strokeaha.113.003606
复制
发表时间：
2014-03-01
期刊：
影响因子：
8.3
通讯作者：
Baud, Olivier
中科院分区：
文献类型：
--
作者：
Charriaut-Marlangue, Christiane;Thao Nguyen;Baud, Olivier
背景和目的缺氧缺血（HI）的最佳治疗方法是恢复缺氧缺血区域的血流。我们的目的是研究是否使用磷酸二酯酶5型抑制剂枸橼酸西地那非增强NO-cGMP信号传导，可以修改脑血流量和减少病变的发展brain.Methods HI诱导P7 Sprague-Dawley大鼠单侧颈动脉闭塞和缺氧，然后无论是PBS或西地那非。通过超声成像和连续多普勒记录测量血流速度，以评估侧支募集情况。通过免疫组织化学分析细胞死亡、血脑屏障完整性和胶质细胞活化。运动行为进行了评价，使用适用于新生animals.Results西地那非柠檬酸盐（10 mg/kg）诱导侧支通畅，减少终端dUTP缺口末端标记阳性细胞，反应性星形胶质细胞增生，和巨噬细胞/小胶质细胞活化后HI 72小时和7天。西地那非还减少了病变部位内末端dUTP缺口末端标记阳性内皮细胞的数量。HI和西地那非治疗后7天，组织损失显着减少，动物恢复运动coordination.Conclusions我们的研究结果强烈表明，枸橼酸西地那非治疗，与脑血流量显着增加，减少HI损伤，提高运动在新生大鼠。西地那非可能是一个有趣的新生儿神经保护治疗策略。
Background and Purpose The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain.Methods HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals.Results Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination.Conclusions Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.