当前位置: X-MOL 学术Acta Pharmacol. Sin. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain.
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2020-03-19 , DOI: 10.1038/s41401-020-0394-6
Ya-Qun Zhou 1 , Dai-Qiang Liu 1 , Shu-Ping Chen 1 , Nan Chen 1 , Jia Sun 1 , Xiao-Mei Wang 1 , Fei Cao 2 , Yu-Ke Tian 1 , Da-Wei Ye 3
Affiliation  

Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg−1· d−1, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg−1· d−1, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.



中文翻译:

Nrf2 激活可改善紫杉醇诱导的神经性疼痛中的机械异常性疼痛。

紫杉醇诱发的神经性疼痛 (PINP) 对目前使用的镇痛药难以治愈。以前的研究表明氧化应激在 PINP 中的关键作用。因为核因子 erythroid-2 相关因子 2 (Nrf2) 被认为是内源性抗氧化防御的关键调节因子,我们在这里探讨了 Nrf2 的激活是否可以减弱 PINP。通过每隔一天腹腔注射紫杉醇(2mg/kg)建立PINP大鼠模型,最终累积剂量为8mg/kg。响应 von Frey 丝刺激的后爪缩回阈值 (PWT) 用于评估机械异常性疼痛。我们表明,单剂量的 Nrf2 激活剂奥替普拉(10、50 和 100 mg/kg)剂量依赖性地减弱已建立的机械异常性疼痛,而重复注射奥替普拉(100 mg·kg −1· d -1 , ip 从第 14 天到第 18 天) 几乎消除了 PINP 大鼠的机械异常性疼痛。预注射 Nrf2 抑制剂葫芦巴碱 (20 mg/kg, ip) 可阻断吡噻硫酮的镇痛作用。早期使用吡噻硫酮治疗(100 mg·kg −1 · d −1, ip 从 d 0 到 d 6) 未能阻止 PINP 的发展,但延迟了它的发作。蛋白质印迹和免疫荧光分析显示,Nrf2 和 HO-1 的表达水平在 PINP 大鼠的脊髓中显着上调。反复注射吡噻硫酮导致 PINP 大鼠脊髓中 Nrf2 和 HO-1 表达水平进一步升高,预注射葫芦巴碱可逆转这种情况。这些结果表明吡噻硫酮通过激活脊髓中的 Nrf2/HO-1 信号通路改善 PINP。

更新日期:2020-04-24
down
wechat
bug