Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke
Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke
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DOI：
10.1016/j.brainres.2006.08.028
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发表时间：
2006-11-06
期刊：
影响因子：
2.9
通讯作者：
Chopp, Michael
中科院分区：
文献类型：
--
作者：
Zhang, Li;Zhang, Zhenggang;Chopp, Michael
西地那非是一种半衰期短的5型磷酸二酯酶同工酶（PDE 5）抑制剂，在卒中后给药时可增加脑环磷酸鸟苷（cGMP）水平，并改善神经功能恢复。在本研究中，我们研究了他达拉非的作用。（Cialis），一种长效PDE 5抑制剂，对栓塞性卒中大鼠模型中卒中恢复期间脑cGMP水平、神经发生、血管生成和神经功能的影响。雄性Wistar大鼠（n = 28）进行栓塞大脑中动脉（MCA）闭塞。从卒中发作后24小时开始，他达拉非以2 mg/kg或10 mg/kg的剂量每48小时经口给药一次，连续给药6天。对照动物在相同时间点接受等体积的生理盐水。对于有丝分裂标记，在中风后5、6和7天每天两次给予溴脱氧尿苷（BrdU，100 mg/kg）。进行ELISA试验以评价他达拉非对cGMP影响的特异性。他达拉非以2或10 mg/kg的剂量治疗显著改善。与盐水处理的大鼠相比，神经功能恢复。此外，与生理盐水处理的大鼠相比，他达拉非处理增加了脑血管密度和缺血边界周围BrdU阳性内皮细胞的百分比。此外，他达拉非给药组大鼠的同侧SVZ细胞增殖程度高于生理盐水给药组大鼠。然而，与生理盐水组相比，他达拉非治疗并没有减少梗死体积。他达拉非选择性增加cGMP，但不增加环磷酸腺苷（cAMP）。我们的数据表明，他达拉非治疗缺血性卒中可改善功能恢复，这与脑cGMP水平升高以及血管生成和神经发生增强相关。(c)2006 Elsevier B. V.保留所有权利。
Sildenafil, a type 5 phosphodiesterase isoenzyme (PDE5) inhibitor with a short half-life, increases brain cyclic guanosine monophosphate (cGMP) levels and improves neurological functional recovery when administered after stroke. In the present study, we investigated the effects of tadalafil. (Cialis), a long acting PDE5 inhibitor, on brain cGMP levels, neurogenesis, angiogenesis, and neurological function during stroke recovery in a rat model of embolic stroke. Male Wistar rats (n = 28) were subjected to embolic middle Cerebral artery (MCA) occlusion. Tadalafil was orally administered every 48 h at a dose of 2 mg/kg or 10 mg/kg for 6 consecutive days starting 24 h after stroke onset. Control animals received the equivalent volume of saline at the same time points. For mitotic labeling, bromodeoxyuridine (BrdU, 100 mg/kg) was administered twice a day at 5, 6, and 7 days after stroke. ELISA assays were performed to evaluate the specificity of the effect of tadalafil on cGMP. Treatment with tadalafil at a dose of 2 or 10 mg/kg significantly improved. neurological functional recovery compared with saline-treated rats. In addition, tadalafil treatment increased cerebral vascular density and the percentage of BrdU-positive endothelial cells around the ischemic boundary compared with saline-treated rats. Moreover, tadalafil treated rats showed greater ipsilateral SVZ cell proliferation than saline-treated rats. However, treatment with tadalafil did not reduce infarct volume when compared to the saline group. Tadalafil selectively increased cGMP but not cyclic adenosine monophosphate (CAMP) in brain. Our data demonstrate that treatment of ischemic stroke with tadalafil improved functional recovery, which was associated with increases of brain cGMP levels and enhancement of angiogenesis and neurogenesis. (c) 2006 Elsevier B.V. All rights reserved.