Minocycline attenuates the development of diabetic neuropathy by inhibiting spinal cord Notch signaling in rat
Minocycline attenuates the development of diabetic neuropathy by inhibiting spinal cord Notch signaling in rat
复制标题
DOI：
10.1016/j.biopha.2017.07.078
复制
发表时间：
2017-10-01
影响因子：
7.5
通讯作者：
Yu, Yonghao
中科院分区：
文献类型：
--
作者：
Yang, Cheng;Gao, Jie;Yu, Yonghao
研究小胶质细胞激活抑制剂米诺环素（minocycline，minocycline）对Notch-1受体表达和活性的影响，探讨米诺环素联合Notch抑制剂DAPT治疗糖尿病神经病理性疼痛（diabetic neuropathic pain，DNP）的疗效。腹腔注射链脲佐菌素（STZ）建立糖尿病大鼠模型。WB法检测Notch-1的表达和活性，巨噬细胞/小胶质细胞标志物Iba-1的表达。糖尿病诱导明显减弱坐骨神经传导速度，并显着增加Notch-1的表达和活性的脊髓腰膨大。然而，米诺环素治疗加速了糖尿病大鼠坐骨神经传导速度的下降，并抑制了Notch-1的表达和活性。与DAPT治疗相似，二甲胺四环素给药也通过抑制脊髓Notch-1的表达和活性延长糖尿病大鼠对热或机械刺激的热退缩潜伏期（TWL）和增加机械退缩阈值（MWT）。DAPT和米诺环素的组合进一步抑制Notch-1受体信号传导并减少神经性疼痛，表现为改善的TWL和MWT。本研究揭示了米诺环素诱导的脊髓Notch-1受体抑制的新机制，提示米诺环素和DAPT联合应用具有治疗DNP的潜力。(C)2017年Elsevier Masson SAS。All rights reserved.
We studied the effects of minocycline (an inhibitor of microglial activation) on the expression and activity of Notch-1 receptor, and explored the therapeutic efficacy of minocycline combined with Notch inhibitor DAPT in the treatment of diabetic neuropathic pain (DNP). Diabetic rat model was established by intraperitoneal injection (ip) of Streptozotocin (STZ). Expression and activity of Notch-1 and expression of macrophage/microglia marker Iba-1 were detected by WB. Diabetes induction significantly attenuated sciatic nerve conduction velocity, and dramatically augmented the expression and the activity of Notch-1 in the lumbar enlargement of the spinal cord. Minocycline treatment, however, accelerated the decreased conduction velocity of sciatic nerve and suppressed Notch-1expression and activity in diabetic rats. Similar to DAPT treatment, minocycline administration also prolonged thermal withdrawal latency (TWL) and increase mechanical withdrawal threshold (MWT) in diabetic rats in response to heat or mechanical stimulation via inhibition the expression and the activity of Notch-1 in spinal cord. Combination of DAPT and minocycline further inhibited Notch-1 receptor signaling and reduce neuropathic pain exhibited as improved TWL and MWT. Our study revealed a novel mechanism of Notch-1 receptor inhibition in spinal cord induced by minocycline administration, and suggested that the combination of minocycline and DAPT has the potential to treat DNP. (C) 2017 Elsevier Masson SAS. All rights reserved.