Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice.
Sildenafil ameliorates long term peripheral neuropathy in type II diabetic mice.
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DOI：
10.1371/journal.pone.0118134
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang ZG
中科院分区：
文献类型：
--
作者：
Wang L;Chopp M;Szalad A;Jia L;Lu X;Lu M;Zhang L;Zhang Y;Zhang R;Zhang ZG
糖尿病周围神经病变是长期糖尿病的常见并发症。为了模拟糖尿病患者患有晚期周围神经病变的临床试验，我们研究了西地那非（一种磷酸二酯酶5型酶的特异性抑制剂）对患有II型糖尿病的中年雄性小鼠长期周围神经病变的影响。用西地那非治疗36周龄的糖尿病小鼠（BKS. Cg-m +/+ Leprdb/J，db/db）显著增加了坐骨神经中的功能性血管和局部血流量，同时增加了皮肤中的表皮内神经纤维密度和坐骨神经中的有髓轴突。功能分析表明，西地那非治疗大大改善运动和感觉传导速度在坐骨神经和外周热刺激敏感性相比，生理盐水治疗。体外研究表明，在高糖水平下培养的小鼠真皮内皮细胞（MDE）表现出显着下调血管生成素1（Ang1）的表达和减少毛细血管样管的形成，这是完全逆转西地那非。此外，背根神经节（DRG）神经元与从MDE收获的条件培养基在高葡萄糖水平下孵育抑制神经突生长，而从MDE收获的条件培养基在高葡萄糖水平下用西地那非处理并不抑制DRG神经元的神经突生长。此外，阻断血管生成素1受体，Tie2，与Tie2的中和抗体废除了西地那非对管形成和神经突生长的有益作用。总的来说，我们的数据表明，西地那非对中年糖尿病小鼠的长期周围神经病变具有治疗作用，并且西地那非对神经血管功能障碍的改善可能有助于神经功能的改善。Ang1/Tie2信号通路可能在这些恢复过程中发挥重要作用。
Diabetic peripheral neuropathy is a common complication of long-standing diabetes mellitus. To mimic clinical trials in which patients with diabetes enrolled have advanced peripheral neuropathy, we investigated the effect of sildenafil, a specific inhibitor of phosphodiesterase type 5 enzyme, on long term peripheral neuropathy in middle aged male mice with type II diabetes. Treatment of diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 36 weeks with sildenafil significantly increased functional blood vessels and regional blood flow in the sciatic nerve, concurrently with augmentation of intra-epidermal nerve fiber density in the skin and myelinated axons in the sciatic nerve. Functional analysis showed that the sildenafil treatment considerably improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal stimulus sensitivity compared with the saline treatment. In vitro studies showed that mouse dermal endothelial cells (MDE) cultured under high glucose levels exhibited significant down regulation of angiopoietin 1 (Ang1) expression and reduction of capillary-like tube formation, which were completely reversed by sildenafil. In addition, incubation of dorsal root ganglia (DRG) neurons with conditioned medium harvested from MDE under high glucose levels suppressed neurite outgrowth, where as conditional medium harvested from MDE treated with sildenafil under high glucose levels did not inhibit neurite outgrowth of DRG neurons. Moreover, blockage of the Ang1 receptor, Tie2, with a neutralized antibody against Tie2 abolished the beneficial effect of sildenafil on tube formation and neurite outgrowth. Collectively, our data indicate that sildenafil has a therapeutic effect on long term peripheral neuropathy of middle aged diabetic mice and that improvement of neurovascular dysfunction by sildenafil likely contributes to the amelioration of nerve function. The Ang1/Tie2 signaling pathway may play an important role in these restorative processes.
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影响因子：
4
作者：
Kim, Hoe Kyu;Kim, Yeon Jeong;Jung, Jin Sup
通讯作者：
Jung, Jin Sup
影响因子：
12.7
作者：
SIMA, AAF;ROBERTSON, DM
通讯作者：
ROBERTSON, DM
影响因子：
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作者：
Charnogursky, Gerald;Lee, Hong;Lopez, Norma
通讯作者：
Lopez, Norma
影响因子：
7.7
作者：
Obrosova, Irina G.;Ilnytska, Olga;Drel, Viktor R.
通讯作者：
Drel, Viktor R.
DOI：
10.1006/bbrc.1999.1586
发表时间：
1999-11-02
影响因子：
3.1
作者：
Lee, OH;Kim, YM;Kwon, YG
通讯作者：
Kwon, YG