Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Bala Nagar, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Bala Nagar, India.
J Nutr Biochem. 2017 Sep;47:41-52. doi: 10.1016/j.jnutbio.2017.05.001. Epub 2017 May 11.
Sirtuin (SIRT1) inactivation underlies the pathogenesis of insulin resistance and hyperglycaemia-associated vascular complications, but its role in diabetic neuropathy (DN) has not been yet explored. We have evaluated hyperglycaemia-induced alteration of SIRT1 signalling and the effect of isoliquiritigenin (ILQ) on SIRT1-directed AMP kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signalling in peripheral nerves of streptozotocin (STZ) (55 mg/kg, ip)-induced diabetic rats and in high glucose (30 mM)-exposed neuro2a (N2A) cells. Diabetic rats and high glucose-exposed N2A cells showed reduction in SIRT1 expression with consequent decline in mitochondrial biogenesis and autophagy. ILQ (10 & 20 mg/kg, po) administration to diabetic rats for 2 weeks and exposure to glucose-insulted N2A cells resulted in significant SIRT1 activation with concurrent increase in mitochondrial biogenesis and autophagy. ILQ administration also enhanced NAD/NADH ratio in peripheral sciatic nerves which explains its possible SIRT1 modulatory effect. Functional and behavioural studies show beneficial effect of ILQ as it alleviated nerve conduction and nerve blood flow deficits in diabetic rats along with improvement in behavioural parameters (hyperalgesia and allodynia). ILQ treatment to N2A cells reduced high glucose-driven ROS production and mitochondrial membrane depolarization. Further, ILQ-mediated SIRT1 activation facilitated the Nrf2-directed antioxidant signalling. Overall, results from this study suggest that SIRT1 activation by ILQ mimic effects of calorie restriction, that is, PGC-1α-mediated mitochondrial biogenesis, FOXO3a mediated stress resistance and AMPK mediated autophagy effects to counteract the multiple manifestations in experimental DN.
Sirtuin (SIRT1)失活是胰岛素抵抗和高血糖相关血管并发症发病机制的基础，但它在糖尿病神经病变 (DN) 中的作用尚未得到探索。我们评估了高血糖诱导的 SIRT1 信号改变，以及异甘草素 (ILQ) 对链脲佐菌素 (STZ) (55 mg/kg，ip) 诱导的糖尿病大鼠周围神经中 SIRT1 定向 AMP 激酶 (AMPK) 和过氧化物酶体增殖物激活受体 γ 共激活物 1-α (PGC-1α) 信号的影响和在高葡萄糖 (30 mM) 暴露的神经 2a (N2A) 细胞。糖尿病大鼠和高葡萄糖暴露的 N2A 细胞 SIRT1 表达减少，导致线粒体生物发生和自噬减少。ILQ (10 和 20 mg/kg，po) 给糖尿病大鼠给药 2 周，暴露于葡萄糖损伤的 N2A 细胞导致 SIRT1 显著激活，同时增加线粒体生物发生和自噬。ILQ 给药还增加了周围坐骨神经中的 NAD/NADH 比值，这解释了其可能的 SIRT1 调节作用。功能和行为研究表明，ILQ 具有有益的作用，因为它减轻了糖尿病大鼠的神经传导和神经血流缺陷，同时改善了行为参数 (痛觉过敏和感觉异常)。ILQ 处理 N2A 细胞减少了高葡萄糖驱动的 ROS 产生和线粒体膜去极化。此外，ILQ 介导的 SIRT1 激活促进了 Nrf2 定向抗氧化信号。总的来说，这项研究的结果表明，ILQ 通过 SIRT1 激活模拟了热量限制的效果，即 PGC-1α 介导的线粒体生物发生、FOXO3a 介导的应激抵抗和 AMPK 介导的自噬效应，以对抗实验性 DN 的多种表现。
