Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab-160062, India.
Neuropharmacology. 2010 Mar;58(3):585-92. doi: 10.1016/j.neuropharm.2009.11.018. Epub 2009 Dec 11.
Oxidative stress resulting in excessive generation of ROS is a compelling initiator of DNA damage along with damage to various cellular proteins and other macromolecules. Poly(ADP-ribose) polymerase (PARP) activation in response to DNA damage, stirs an energy-consuming cellular metabolic cycle; culminating into cell death. The present study was designed to determine the effect of combining an antioxidant, Melatonin and a PARP inhibitor, Nicotinamide on the hallmark deficits developing in diabetic neuropathy (DN). Streptozotocin (STZ, 55 mg/kg, i.p.) was administered to induce diabetes. Six weeks post diabetes induction, two week treatment with Melatonin (3 and 10 mg/kg) and Nicotinamide (100 and 300 mg/kg) either alone or in combination was given. Effect of these interventions on the functional, behavioral and biochemical changes caused by hyperglycemia were studied in treated animals. Melatonin and Nicotinamide alone as well as in combination ameliorated the functional deficits along with improvement in pain parameters. The combination also demonstrated an essential reversal of biochemical alterations. Nitrotyrosine and Poly ADP Ribose (PAR) immunopositivity was significantly decreased in sciatic nerve micro-sections of treatment group. The results of this study advocate that simultaneous inhibition of oxidative stress-PARP activation cascade may prove useful for the pharmacotherapy of DN.
氧化应激导致活性氧（ROS）的过度产生，是 DNA 损伤以及各种细胞蛋白和其他大分子损伤的一个主要启动因素。DNA 损伤时，多聚（ADP-核糖）聚合酶（PARP）的激活会引发一个耗能的细胞代谢循环，最终导致细胞死亡。本研究旨在确定抗氧化剂褪黑素和 PARP 抑制剂烟酰胺联合应用对糖尿病神经病变（DN）标志性缺陷发展的影响。链脲佐菌素（STZ，55mg/kg，腹腔注射）用于诱导糖尿病。糖尿病诱导 6 周后，单独或联合给予褪黑素（3 和 10mg/kg）和烟酰胺（100 和 300mg/kg）进行为期 2 周的治疗。研究这些干预措施对高血糖引起的功能、行为和生化变化的影响。褪黑素和烟酰胺单独以及联合应用均改善了功能缺陷，并改善了疼痛参数。该联合治疗还显示出对生化改变的重要逆转。坐骨神经微切片中的硝基酪氨酸和聚 ADP 核糖（PAR）免疫阳性显著减少。这项研究的结果表明，同时抑制氧化应激-PARP 激活级联反应可能对糖尿病神经病变的药物治疗有用。
