Komirishetty Prashanth, Areti Aparna, Gogoi Ranadeep, Sistla Ramakrishna, Kumar Ashutosh
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India; Division of Neurology, Department of Medicine, University of Alberta, 2E3.26 Walter C Mackenzie, Health Sciences Center, Edmonton, AB, T6G 2B7, Canada.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
Neuropharmacology. 2017 Feb;113(Pt A):137-147. doi: 10.1016/j.neuropharm.2016.09.027. Epub 2016 Oct 3.
Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats. Quercetin (25 mg/kg, p.o.) and 4-ANI (3 mg/kg, p.o.) were administered either alone or in combination for 14 days to examine sciatic functional index, allodynia and hyperalgesia using walking track analysis, Von Frey, acetone spray and hot plate tests respectively. Malondialdehyde, nitrite and glutathione levels were estimated to detect oxidative/nitrosative stress; mitochondrial membrane potential and cytochrome c oxidase activity to assess mitochondrial function; NAD & ATP levels to examine the bioenergetic status and levels of inflammatory markers were evaluated in ipsilateral sciatic nerve. Quercetin and 4-ANI alone improved the pain behaviour and biochemical alterations but the combination therapy demonstrated an appreciable reversal of CCI-induced changes. Nitrotyrosine and Poly ADP-Ribose (PAR) immunopositivity was decreased and nuclear factor erythroid 2-related factor (Nrf-2) levels were increased significantly in micro-sections of the sciatic nerve and dorsal root ganglion (DRG) of treatment group. These results suggest that simultaneous inhibition of oxidative stress-PARP activation cascade may potentially be useful strategies for management of trauma induced neuropathic pain.
神经性疼痛是一种使人衰弱的疼痛病症，其潜在的致病机制复杂且相互交织，然而关于有望治疗该病症的疗法，目前仍缺乏相关信息。有证据表明，氧化/亚硝化应激诱导的聚（ADP-核糖）聚合酶（PARP）过度激活会引发神经炎症和生物能量危机，最终在神经损伤后导致神经退行性变化。因此，我们研究了抗氧化剂槲皮素和PARP抑制剂4-氨基-1,8-萘二甲酰亚胺（4-ANI）联合使用对大鼠坐骨神经慢性缩窄损伤（CCI）所致标志性缺陷的治疗效果。分别单独或联合给予槲皮素（25mg/kg，口服）和4-ANI（3mg/kg，口服）14天，通过行走轨迹分析、von Frey试验、丙酮喷雾试验和热板试验分别检测坐骨神经功能指数、异常性疼痛和痛觉过敏。测定丙二醛、亚硝酸盐和谷胱甘肽水平以检测氧化/亚硝化应激；测定线粒体膜电位和细胞色素c氧化酶活性以评估线粒体功能；测定NAD和ATP水平以检查生物能量状态，并评估同侧坐骨神经中炎症标志物的水平。单独使用槲皮素和4-ANI可改善疼痛行为和生化改变，但联合治疗对CCI诱导的变化有明显的逆转作用。治疗组坐骨神经和背根神经节（DRG）的显微切片中，硝基酪氨酸和聚ADP-核糖（PAR）免疫阳性降低，核因子红细胞2相关因子（Nrf-2）水平显著升高。这些结果表明，同时抑制氧化应激-PARP激活级联反应可能是治疗创伤性神经性疼痛的潜在有效策略。
