Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation.
Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation.
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Notch1信号传导通过促进小胶质细胞激活和神经炎症而导致与环磷酰胺诱发的膀胱炎相关的机械性异常性疼痛
DOI：
10.1155/2021/1791222
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发表时间：
2021
影响因子：
4.6
通讯作者：
Xiao H
中科院分区：
文献类型：
--
作者：
Chen J;Ding H;Liu B;Zhou X;Zhou X;Lin Z;Yang F;Zhan H;Xiao H
Notch 1信号调节小胶质细胞活化，促进神经炎症。神经炎症在各种疼痛感觉中起重要作用，包括膀胱疼痛综合征/间质性膀胱炎（BPS/IC）中的膀胱相关疼痛。然而，Notch 1信号传导对环磷酰胺诱导的膀胱炎中机械性异常性疼痛的影响尚不清楚。本研究旨在确定Notch 1信号是否以及如何调节CYP诱导的膀胱炎的机械性异常性疼痛。方法采用腹腔注射法建立膀胱疼痛综合征/间质性膀胱炎（BPS/IC）大鼠模型。鞘内注射γ-分泌酶抑制剂DAPT以间接调节Notch 1信号传导。用vonFrey细丝测量下腹部机械性缩足阈。采用免疫印迹法和免疫荧光染色法检测L 6-S1脊髓背角（SDH）中Notch 1信号通路、Iba-1、OX-42、TNF-α和IL-1β的表达。结果膀胱炎组SDH中Notch 1和Notch胞内结构域（NICD）均表达上调。Notch 1和NICD的表达与膀胱炎大鼠的机械缩痛阈值呈负相关。此外，DAPT治疗减轻CYP诱导的膀胱炎中的机械性异常性疼痛，并抑制小胶质细胞活化，导致TNF-α和IL-1β的产生减少。结论Notch 1信号通过促进小胶质细胞活化和神经炎症反应参与CYP诱导的膀胱炎相关的机械性异常性疼痛。我们的研究表明，抑制Notch 1信号可能对治疗BPS/IC的疼痛症状具有治疗价值。
Aims Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis. Methods CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A γ-secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-α, and IL-1β in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining. Results Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF-α and IL-1β. Conclusion Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.
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DOI：
10.1152/ajprenal.00017.2019
发表时间：
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影响因子：
4.2
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