Zhang Ruilan, Wang Ying, Zhang Li, Zhang Zhenggang, Tsang Wayne, Lu Mei, Zhang Lijie, Chopp Michael
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Mich, USA.
Stroke. 2002 Nov;33(11):2675-80. doi: 10.1161/01.str.0000034399.95249.59.
We tested the hypothesis that sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, promotes functional recovery and neurogenesis after stroke.
Male Wistar rats were subjected to embolic middle cerebral artery occlusion. Sildenafil (Viagra) was administered orally for 7 consecutive days starting 2 or 24 hours after stroke onset at doses of 2 or 5 mg/kg per day. Ischemic rats administered the same volume of tap water were used as a control group. Functional outcome tests (foot-fault, adhesive removal) were performed. Rats were killed 28 days after stroke for analysis of infarct volume and newly generated cells within the subventricular zone and the dentate gyrus. Brain cGMP levels, expression of PDE5, and localized cerebral blood flow were measured in additional rats.
Treatment with sildenafil significantly (P<0.05) enhanced neurological recovery in all tests performed. There was no significant difference of infarct volume among the experimental groups. Treatment with sildenafil significantly (P<0.05) increased numbers of bromodeoxyuridine-immunoreactive cells in the subventricular zone and the dentate gyrus and numbers of immature neurons, as indicated by betaIII-tubulin (TuJ1) immunoreactivity in the ipsilateral subventricular zone and striatum. The cortical levels of cGMP significantly increased after administration of sildenafil, and PDE5 mRNA was present in both nonischemic and ischemic brain.
Sildenafil increases brain levels of cGMP, evokes neurogenesis, and reduces neurological deficits when given to rats 2 or 24 hours after stroke. These data suggest that this drug that is presently in the clinic for sexual dysfunction may have a role in promoting recovery from stroke.
我们验证了如下假设，即5型磷酸二酯酶（PDE5）抑制剂西地那非可促进卒中后的功能恢复及神经发生。
雄性Wistar大鼠接受栓塞性大脑中动脉闭塞手术。卒中发作后2小时或24小时起，连续7天口服给予西地那非（万艾可），剂量为每天2或5毫克/千克。给予相同体积自来水的缺血大鼠作为对照组。进行功能结局测试（足误、黏附去除）。卒中后28天处死大鼠，分析梗死体积以及脑室下区和齿状回内的新生细胞。在另外的大鼠中测量脑cGMP水平、PDE5表达及局部脑血流量。
在所有进行的测试中，西地那非治疗均显著（P<0.05）促进了神经功能恢复。各实验组之间梗死体积无显著差异。西地那非治疗显著（P<0.05）增加了脑室下区和齿状回中溴脱氧尿苷免疫反应性细胞的数量，以及同侧脑室下区和纹状体中βIII微管蛋白（TuJ1）免疫反应性所显示的未成熟神经元数量。给予西地那非后，皮质cGMP水平显著升高，且PDE5 mRNA在非缺血和缺血脑中均有表达。
卒中后2小时或24小时给予大鼠西地那非，可增加脑内cGMP水平，引发神经发生，并减少神经功能缺损。这些数据表明，这种目前用于治疗性功能障碍的药物可能在促进卒中恢复方面发挥作用。
