Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation.

Jialiang Chen,Xiangfu Zhou,Zhijun Lin,Honglu Ding,Hengjun Xiao,Hailun Zhan,Bolong Liu,Fei Yang,Xin Zhou,Marcella Reale

doi:10.1155/2021/1791222

Abstract

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.

Highlights

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a syndrome complex characterized by bladder-related pain associated with lower urinary tract symptoms, mainly urinary frequency and urgency [1]
We revealed that Notch1 signaling was upregulated in the L6-S1 spinal dorsal horn (SDH) of the CYP-induced cystitis rat model, and the expression of Notch1 and Notch intracellular domain (NICD) was negatively correlated with the mechanical withdrawal threshold of the cystitis animals
Visceral pain is different from neuropathic pain to some extent, we found in our previous studies [5, 20, 21] that neuroinflammation in the central nervous system including SDH and the hippocampus could be an underlying mechanism of bladder-related pain in a cystitis rat model

Summary

Introduction

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a syndrome complex characterized by bladder-related pain associated with lower urinary tract symptoms, mainly urinary frequency and urgency [1]. A clinical cohort study revealed that most BPS/IC female patients suffer from constant pain for more than five years [2]. As the dominating symptom of BPS/IC, unrelieved chronic pain can potentiate severe psychological comorbidities, including depression and anxiety, which further aggravate a patient’s quality of life [3]. The mechanism of bladder-related pain is still unclear, accounting for the limited therapeutic strategies for BPS/IC. It is of great clinical importance to clarify the mechanism based on which to provide therapeutic targets for BPS/IC. The activated microglia can produce more proinflammatory cytokines such as TNF-α and IL-1β.

Methods

Results

Discussion

Conclusion