转位蛋白的激活通过抑制 BDNF 介导体液炎症反应缓解环磷酰胺诱导的膀胱炎所致的机械性痛觉过敏和膀胱功能障碍。

Activation of translocator protein alleviates mechanical allodynia and bladder dysfunction in cyclophosphamide-induced cystitis through repression of BDNF-mediated neuroinflammation.

机构信息

Department of Urology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.

Department of Rehabilitation, the Third Affiliated Hospital and Lingnan Hospital of the Sun Yat-Sen University, Guangzhou, China.

出版信息

Eur J Pain. 2022 Jul;26(6):1234-1244. doi: 10.1002/ejp.1942. Epub 2022 Mar 28.

DOI:10.1002/ejp.1942

PMID:35293071

Abstract

BACKGROUND

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a refractory disease accompanied by bladder-related pain and hyperactivity. Studies have shown that the translocator protein (TSPO) modulates neuroinflammation and central sensitisation associated with pain. Moreover, we previously demonstrated that brain-derived neurotrophic factor (BDNF) regulates neuroinflammation and mechanical allodynia in cyclophosphamide (CYP)-induced cystitis through activation of glial cells. Here, we aimed to explore whether activation of TSPO attenuates mechanical allodynia and bladder dysfunction by regulating BDNF induced neuroinflammation in a CYP-induced cystitis model.

METHODS

Injection of CYP was performed to form a rat model of BPS/IC. The expression of TSPO was regulated by intrathecal injection of the TSPO agonist Ro5-4864. The von Frey filament test was applied to evaluate suprapubic allodynia. Bladder function was assessed using filling cystometry. Western blotting was used to detect the expression of TSPO, BDNF, GFAP, Iba-1, p-p38, p-JNK, TNF-α, and IL-1β, and double immunofluorescence was performed to localise TSPO in the L6-S1 spinal dorsal horn (SDH).

RESULTS

TSPO was activated in the SDH after CYP injection and was primarily colocalised with astrocytes. Ro5-4864 reversed mechanical allodynia and bladder dysfunction induced by CYP. Moreover, the upregulation of BDNF and activation of astrocytes and microglia was suppressed by Ro5-4864, resulting in downregulation of p-p38, p-JNK, TNF-α, and IL-1β.

CONCLUSIONS

Ro5-4864 alleviated mechanical allodynia and bladder dysfunction in the CYP model, possibly by inhibiting the elevation of BDNF and consequent activation of astrocytes and microglia induced neuroinflammation. TSPO may be a potential target for the treatment of BPS/IC.

SIGNIFICANCE

This study examined the mechanism underlying the ability of the translocator protein to modulate bladder pain syndrome/interstitial cystitis.

摘要

背景

膀胱疼痛综合征/间质性膀胱炎（BPS/IC）是一种伴有膀胱相关疼痛和过度活动的难治性疾病。研究表明，转位蛋白（TSPO）调节与疼痛相关的神经炎症和中枢敏化。此外，我们之前的研究表明，脑源性神经营养因子（BDNF）通过激活神经胶质细胞调节环磷酰胺（CYP）诱导的膀胱炎中的神经炎症和机械性痛觉过敏。在这里，我们旨在探讨 TSPO 激活是否通过调节 CYP 诱导的膀胱炎中 BDNF 诱导的神经炎症来减轻机械性痛觉过敏和膀胱功能障碍。

方法

注射 CYP 构建大鼠 BPS/IC 模型。通过鞘内注射 TSPO 激动剂 Ro5-4864 调节 TSPO 的表达。应用 Von Frey 细丝试验评估耻骨上痛觉过敏。使用充盈膀胱测压法评估膀胱功能。采用 Western blot 检测 TSPO、BDNF、GFAP、Iba-1、p-p38、p-JNK、TNF-α和 IL-1β的表达，并进行双免疫荧光定位 TSPO 在 L6-S1 脊髓背角（SDH）中的表达。