BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis

Honglu Ding,Zhijun Lin,Bolong Liu,Xiangfu Zhou,Yong Huang,Wenbiao Li,Xianguo Liu,Juncong Xie,Hailun Zhan,Fei Yang,Minzhi Su,Jialiang Chen

doi:10.1186/s12974-020-1704-0

Abstract

BackgroundPatients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs.MethodsSystemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis.ResultsBDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1β in the SDH of our CYP-induced cystitis model.ConclusionsIn our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1β, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.

Highlights

Patients with interstitial cystitis/bladder pain syndrome (IC/Bladder pain syndrome (BPS)) often grieve over a low quality of life brought about by chronic pain
We conducted a Western blot analysis to measure the expression of brain-derived neurotrophic factor (BDNF)-Tyrosine-protein kinase B (TrkB) signaling in the spinal dorsal horn (SDH), and found that BDNF, TrkB, and p-TrkB were upregulated on days 8, 12, and 17 after the first CYP injection in the group with cystitis (Fig. 1b–d)
We conducted an immunofluorescence double staining assay to evaluate the localization of BDNF and p-TrkB in the SDH of the cystitis model

Summary

Introduction

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. Interstitial cystitis/bladder pain syndrome (IC/BPS) is an enigmatic chronic inflammatory disease of the bladder. It is characterized by bladder pain accompanied with frequency, urgency, nocturia, and sterile urine, excluding typical urinary tract infections [1,2,3]. A communitybased study in the USA reported a high prevalence rate of BPS, 2.7–6.5% in women, and 2–4% in men [4, 5] These rates typically vary between 6 and 32% in different countries [6]. A variety of theories have been proposed, including bladder urothelial defects or dysfunction, mast cell activation and autoimmunity, the etiology and pathophysiology remain largely unexplored [2, 7]

Objectives

Methods

Results

Conclusion