Downregulation of glucose-6-phosphate dehydrogenase contributes to diabetic neuropathic pain through upregulation of toll-like receptor 4 in rats
Downregulation of glucose-6-phosphate dehydrogenase contributes to diabetic neuropathic pain through upregulation of toll-like receptor 4 in rats
复制标题
大鼠体内葡萄糖-6-磷酸脱氢酶的下调通过上调 Toll 样受体 4 导致糖尿病神经性疼痛
DOI：
10.1177/1744806919838659
复制
发表时间：
2019-04-01
期刊：
影响因子：
3.3
通讯作者：
Xu, Guang-Yin
中科院分区：
文献类型：
--
作者：
Sun, Qian;Zhang, Bing-Yu;Xu, Guang-Yin
背景和目的糖尿病神经病理性疼痛是糖尿病的一种难治性和致残性并发症。糖尿病神经病理性疼痛的发病机制尚不清楚，治疗也不充分。本研究旨在探讨葡萄糖-6-磷酸脱氢酶（G6 PD）和Toll样受体4（TLR 4）在糖尿病大鼠神经病理性疼痛中的作用。方法成年雌性SD大鼠腹腔注射链脲佐菌素（STZ）75 mg/kg建立1型糖尿病模型。分别用von Frey细丝法和热辐射法测定大鼠缩足阈和缩足潜伏期。采用Western blotting和实时荧光定量聚合酶链反应技术检测L4-L 6背根神经节（DRG）G6 PD和TLR 4的表达。采用免疫荧光法检测G6 PD、TLR 4的表达及G6 PD与TLR 4的共定位。结果糖尿病大鼠背根节G6 PD mRNA和蛋白表达水平均明显低于同龄对照组。鞘内注射G6 PD过表达腺病毒上调G6 PD表达可明显减轻糖尿病大鼠后爪疼痛敏感性。与对照组相比，糖尿病大鼠DRG中TLR 4的mRNA和蛋白表达水平均显著升高。鞘内注射TLR 4选择性抑制剂CLI-095以剂量和时间依赖性方式减轻糖尿病疼痛。此外，G6 PD和TLR 4共定位于DRG神经元。鞘内注射G6 PD过表达腺病毒可显著降低糖尿病大鼠TLR 4表达，而鞘内注射CLI-095对糖尿病大鼠G6 PD表达无明显影响。结论糖尿病周围神经病理性痛大鼠G6 PD表达降低，可能通过上调背根神经节TLR 4表达而发生。
Background and aim Diabetic neuropathic pain is a refractory and disabling complication of diabetes mellitus. The pathogenesis of the diabetic neuropathic pain is still unclear, and treatment is insufficient. The aim of this study is to investigate the roles of glucose-6-phosphate dehydrogenase (G6PD) and toll-like receptor 4 (TLR4) in neuropathic pain in rats with diabetes. Methods Type 1 diabetes model was induced by intraperitoneal injection of streptozotocin (STZ, 75 mg/kg) in adult female Sprague-Dawley rats. Paw withdrawal threshold and paw withdrawal latency of rats were measured by von Frey filaments and thermal radiation, respectively. The expressions of G6PD and TLR4 in L4-L6 dorsal root ganglions (DRGs) were measured by western blotting and quantitative real-time polymerase chain reaction analysis. Fluorescent immunohistochemistry was employed to detect expressions of G6PD and TLR4 and co-location of G6PD with TLR4. Results The mRNA and protein expression levels of G6PD in DRGs were significantly decreased in diabetic rats when compared with age-matched control rats. Upregulation of G6PD by intrathecal injection of G6PD overexpression adenovirus markedly attenuated hindpaw pain hypersensitivity of diabetic rats. The mRNA and protein expression levels of TLR4 in DRGs of diabetic rats were significantly increased when compared with control rats. Intrathecal injection of TLR4-selective inhibitor CLI-095 attenuated diabetic pain in dose- and time-dependent manners. Furthermore, G6PD and TLR4 were co-localized in DRG neurons. Intrathecal injection of G6PD overexpression adenovirus greatly reduced TLR4 expression, while intrathecal injection of CLI-095 had no significant effect on G6PD expression in diabetic rats. Conclusions Our results suggest that decrease in G6PD expression was involved in diabetic peripheral neuropathic pain, which was most likely through upregulation of TLR4 expression in the DRGs of rats.