Diabetes Worsens Functional Outcomes in Young Female Rats: Comparison of Stroke Models, Tissue Plasminogen Activator Effects, and Sexes.
Diabetes Worsens Functional Outcomes in Young Female Rats: Comparison of Stroke Models, Tissue Plasminogen Activator Effects, and Sexes.
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DOI：
10.1007/s12975-017-0525-7
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发表时间：
2017-03-01
影响因子：
6.9
通讯作者：
Ergul A
中科院分区：
文献类型：
--
作者：
Li W;Ward R;Valenzuela JP;Dong G;Fagan SC;Ergul A
糖尿病会使中风结果恶化，并增加缺血性中风后出血性转化（HT）的风险，尤其是在组织纤溶酶原激活剂（tPA）治疗时。由于担心出血性转化 (HT)，tPA 的广泛使用仍然受到限制，临床前研究正在积极探索其潜在机制。然而，实验模型使用的 tPA 剂量比临床剂量 (10 mg/kg) 高 10 倍，并且大多仅使用雄性动物。在这项转化研究中，我们假设低剂量 tPA 将改善对照动物和糖尿病雄性和雌性动物栓塞性中风后的功能恢复。用高脂肪饮食和低剂量链脲佐菌素（30 mg/kg，腹膜内注射）诱导年龄匹配的雄性和雌性 Wistar 大鼠患糖尿病。大脑中动脉（MCA）的血栓闭塞诱发栓塞性中风。手术后 90 分钟，用或不用 tPA（1 mg/kg，静脉注射）对动物进行治疗。另外一组动物用缝合线进行 90 分钟的 MCAO。术后 3 天评估神经功能缺损（综合评分和粘合剂去除试验-ART）、梗塞面积、水肿比率和 HT 指数。在对照组中，雌性大鼠的梗塞面积较小，功能结果较好。 tPA 可以减少两性的梗塞面积，其中对男性的影响更大。虽然未使用 tPA 的男性和女性之间的 HT 没有差异，但女性 + tPA 组的 HT 较低。在糖尿病组中，雌性大鼠的神经元损伤增加，达到雄性大鼠的梗死面积。 tPA 可以减少女性的梗塞面积，但不能减少男性的梗塞面积。雌性大鼠的 HT 高于雄性大鼠，并且 tPA 不会进一步增加。糖尿病使两性的神经功能缺陷恶化。雄性动物的感觉运动技能有所改善，尤其是经过 tPA 治疗后，但雌性动物的感觉运动技能没有改善。这些数据表明，糖尿病会加剧两性的神经血管损伤和神经功能缺损。人用剂量的 tPA 对雄性大鼠提供一定程度的保护，但对雌性大鼠则不然。鉴于与雄性大鼠相比，对照雌性动物受到的伤害较少，因此糖尿病对雌性的影响更为深远。
Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tissue plasminogen activator (tPA) treatment. The widespread use of tPA is still limited by the fear of hemorrhagic transformation (HT) and underlying mechanisms are actively being pursued in preclinical studies. However, experimental models use a 10 times higher dose of tPA than the clinical dose (10 mg/kg) and mostly employ only male animals. In this translational study, we hypothesized that low dose tPA will improve the functional recovery after the embolic stroke in both control and diabetic male and female animals. Diabetes was induced in age matched male and female Wistar rats with high fat diet and low dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with clot occlusion of the middle cerebral artery (MCA). The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. An additional set of animals were subjected to 90 min MCAO with suture. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. In the control groups, female rats had smaller infarcts and better functional outcomes. tPA decreased infarct size in both sexes with a greater effect in males. While there was no difference in HT between males and females without tPA, HT was less in the female + tPA group. In the diabetic groups, neuronal injury increased in females reaching that of the infarct sizes seen in male rats. tPA decreased infarct size in females but not males. HT was greater in female rats than in males and was not further increased with tPA. Diabetes worsened neurological deficits in both sexes. Male animals showed improved sensorimotor skills, especially with tPA treatment, but there was no improvement in females. These data suggest that diabetes amplifies neurovascular injury and neurological deficits in both sexes. Human dose tPA offers some degree of protection in male but not female rats. Given that control female animals experience less injury compared to male rats, the diabetes effect is more profound in females.
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影响因子：
8.3
作者：
Fan X;Qiu J;Yu Z;Dai H;Singhal AB;Lo EH;Wang X
通讯作者：
Wang X
影响因子：
8.3
作者：
Li Q;Atochin D;Kashiwagi S;Earle J;Wang A;Mandeville E;Hayakawa K;d'Uscio LV;Lo EH;Katusic Z;Sessa W;Huang PL
通讯作者：
Huang PL
影响因子：
8.3
作者：
Fan X;Ning M;Lo EH;Wang X
通讯作者：
Wang X
影响因子：
6.9
作者：
Hafez, Sherif;Hoda, Md Nasrul;Guo, Xinyue;Johnson, Maribeth H.;Fagan, Susan C.;Ergul, Adviye
通讯作者：
Ergul, Adviye
影响因子：
6.3
作者：
Haelewyn, Benoit;Risso, Jean-Jacques;Abraini, Jacques H.
通讯作者：
Abraini, Jacques H.