BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis
BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis
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BDNF 促进星形胶质细胞和小胶质细胞的活化，导致环磷酰胺诱发的膀胱炎中的神经炎症和机械性异常性疼痛
DOI：
10.1186/s12974-020-1704-0
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发表时间：
2020-01-13
影响因子：
9.3
通讯作者：
Zhou, Xiangfu
中科院分区：
文献类型：
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作者：
Ding, Honglu;Chen, Jialiang;Zhou, Xiangfu
背景间质性膀胱炎/膀胱疼痛综合征（IC/BPS）患者常因慢性疼痛导致的生活质量低下而感到悲伤。在我们以前的研究中，我们确定脊髓背角（SDH）的神经炎症与间质性膀胱炎的机制有关。此外，已显示脑源性神经营养因子（BDNF）通过BDNF-TrkB信号传导参与神经炎症和病理性疼痛的调节;然而，其是否在环磷酰胺（CTX）诱导的膀胱炎中起作用仍不清楚。本研究旨在确认是否BDNF-TrkB信号转导调节CYP诱导的膀胱炎神经炎症和机械异常性疼痛，并确定它是如何发生的。通过腹膜内注射TrkB受体拮抗剂ANA-12或鞘内注射外源性BDNF来调节BDNF-TrkB信号传导。使用von Frey细丝测试评估耻骨上区域的机械性异常性疼痛。采用免疫印迹和免疫荧光法检测L 6-S1 SDH中BDNF、TrkB、p-TrkB、Iba 1、GFAP、p-p38、p-JNK、IL-1β和TNF-α的表达。SDH中Iba 1、GFAP、p-p38、p-JNK、IL-1β和TNF-α的表达均上调。ANA-12治疗可减轻机械性痛觉超敏，抑制星形胶质细胞和小胶质细胞的活化，减轻神经炎症。鞘内注射外源性BDNF可进一步降低CYP诱导的大鼠膀胱炎模型的机械性缩痛阈值，促进星形胶质细胞和小胶质细胞的活化，增加SDH中TNF-α和IL-1 β的释放。加重神经炎症并通过BDNF-TrkB-p38/JNK信号传导导致机械性异常性疼痛。
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.