Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy
Low-dose poly(ADP-ribose) polymerase inhibitor-containing combination therapies reverse early peripheral diabetic neuropathy
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DOI：
10.2337/diabetes.54.5.1514
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发表时间：
2005-05-01
期刊：
影响因子：
7.7
通讯作者：
Obrosova, IG
中科院分区：
文献类型：
--
作者：
Li, F;Drel, VR;Obrosova, IG
聚（ADP-核糖）聚合酶（PARP）抑制最近被确定为治疗实验性周围糖尿病神经病变（PDN）的新方法。然而，长期抑制 PARP（一种参与 DNA 修复的酶）可能会导致过早衰老、基因组稳定性丧失和其他副作用。本研究评估了早期 PDN 模型中低剂量的强效特异性 PARP 抑制剂 1,5-异喹啉二醇 (ISO) 与两种血管扩张剂之一、ACE 抑制剂赖诺普利 (LIS) 和 β(2)-肾上腺素受体激动剂沙丁胺醇 (SAL) 之间的潜在协同相互作用。对照组和链脲佐菌素 (STZ) 诱导的糖尿病大鼠在最初 2 周不治疗后，用 ISO 加 LIS 或 ISO 加 SAL 治疗 2 周。 ISO（腹膜内注射）以及 LIS 和 SAL（均在饮用水中）以亚治疗剂量使用，当作为单一疗法施用时，可轻微纠正与糖尿病相关的坐骨运动和后肢指感觉神经传导缺陷。两种联合治疗均纠正了 STZ 诱导的糖尿病大鼠的神经内血流和血管电导缺陷。 ISO 加 SAL 纠正了 PDN 的所有其他变化，即运动神经传导速度 (MNCV) 和感觉神经传导速度 (SNCV) 缺陷以及热和机械痛觉过敏。使用 ISO 加 LIS，没有观察到 MNCV 的显着校正，并且对热痛觉过敏的影响相当适度。 SNCV 和机械性痛觉过敏得到纠正。人内皮细胞和雪旺细胞的体外研究表明，高葡萄糖会导致聚（ADP-核糖基）化蛋白的早期积累（蛋白质印迹分析），从而表明 PARP 激活在人 PDN 中的重要性。总之，低剂量含PARP抑制剂的联合疗法可能构成治疗PDN的新方法。
Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN). However, long-term inhibition of PARP, an enzyme involved in DNA repair, can potentially result in premature aging, loss of genome stability, and other side effects. This study evaluated potential synergistic interactions between low doses of the potent and specific PARP inhibitor 1,5-isoquinolinediol (ISO) and one of two vasodilators, the ACE inhibitor lisinopril (LIS) and the beta(2)-adrenoceptor agonist salbutamol (SAL) in the model of early PDN. Control and streptozotocin (STZ)-induced diabetic rats were treated with either ISO plus LIS or ISO plus SAL for 2 weeks after an initial 2 weeks without treatment. ISO (intraperitoneally) and LIS and SAL (both in the drinking water) were used in subtherapeutic doses, resulting in a minor correction of diabetes-associated sciatic motor and hind-limb digital sensory nerve conduction deficits when administered as monotherapies. Both combination treatments corrected endoneurial blood flow and vascular conductance deficits in STZ-induced diabetic rats. ISO plus SAL corrected all other changes of PDN, i.e., motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) deficits as well as thermal and mechanical hyperalgesia. With ISO plus LIS, no significant correction of MNCV was observed, and the effect on thermal hyperalgesia was quite modest. SNCV and mechanical hyperalgesia were corrected. In vitro studies in human endothelial and Schwann cells showed early accumulation of poly(ADP-ribosyl)ated proteins (Western blot analysis) in response to high glucose, thus suggesting the importance of PARP activation in human PDN. In conclusion, low-dose PARP inhibitor-containing combination therapies may constitute a new approach for treatment of PDN.