Diabetic neuropathy (DN) is a common complication of diabetes mellitus (DM). Pathophysiology of DN includes inflammation and changes in expression and function of voltage-gated sodium channels (Nav) in peripheral nerves; and central reduction of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) expression. AIM This study explored the effect of ranolazine (RN) versus pioglitazone (PIO) in DN induced in rats. The role of sciatic interleukin (IL)-1β, tumor necrosis factor-alpha (TNF)-α, Nav1.7, and spinal PPAR-γ expressions were determined. MATERIALS AND METHODS For induction of Type-2 DM, 40 high fat diet-fed rats were challenged by a single dose of intraperitoneal streptozotocin (30 mg/kg). One week later, oral PIO (10 mg/kg; once daily) or RN (20, 50 and 100 mg/kg; twice daily) were administered for six weeks. Weekly body weight and fasting blood sugar (FBS) were measured. Rats were tested for thermal hyperalgesia and mechanical allodynia. At the end of the experiment, sciatic nerves homogenates were examined for TNF-α and IL-1B levels, and Nav1.7 channel expression. Segments of spinal cords were investigated for the PPAR-γ gene expression. Evaluation of histopathology of sciatic nerves and spinal cords were done. KEY FINDINGS In diabetic rats, PIO and RN individually improved evoked-pain behaviors, reduced sciatic TNF-α and 1L-1B levels; downregulated expressional levels of Nav1.7 channels; and increased the spinal PPAR-γ gene expression. RN in the dose of 100 mg/kg/day showed the most advantageous effects. SIGNIFICANCE RN has neuroprotective effects in Type-2 diabetes-induced DN. Further studies of combined RN-PIO treatment are recommended, especially in diabetic patients with cardiovascular co-morbidity.

中文翻译：

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雷诺嗪与吡格列酮在实验性糖尿病神经病变中的神经保护作用：靶向Nav1.7通道和PPAR-γ。

糖尿病性神经病（DN）是糖尿病（DM）的常见并发症。DN的病理生理学包括炎症以及周围神经中电压门控钠通道（Nav）的表达和功能的改变。和过氧化物酶体增殖物激活受体-γ（PPAR-γ）表达的集中减少。目的本研究探讨了雷诺嗪（RN）与吡格列酮（PIO）在大鼠DN中的作用。确定了坐骨神经白介素（IL）-1β，肿瘤坏死因子-α（TNF）-α，Nav1.7和脊柱PPAR-γ表达的作用。材料和方法为诱导2型DM，用单剂量腹膜内链脲佐菌素（30 mg / kg）攻击40只高脂饮食喂养的大鼠。一周后，口服口服PIO（10 mg / kg；每天一次）或RN（20、50和100 mg / kg；每天两次），持续6周。每周测量体重和空腹血糖（FBS）。测试大鼠的热痛觉过敏和机械性异常性疼痛。实验结束时，检查坐骨神经匀浆的TNF-α和IL-1B水平以及Nav1.7通道表达。研究脊髓节段的PPAR-γ基因表达。评估坐骨神经和脊髓的组织病理学。主要发现在糖尿病大鼠中，PIO和RN分别改善了诱发痛行为，降低了坐骨神经TNF-α和1L-1B的水平。Nav1.7通道的表达水平下调；并增加了脊髓PPAR-γ基因的表达。RN剂量为100 mg / kg / day时显示出最有利的作用。意义RN对2型糖尿病诱发的DN具有神经保护作用。建议进一步研究RN-PIO联合治疗，