Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis

Liu, Bolong; Su, Minzhi; Tang, Shao-Jun; Zhou, Xiangfu; Zhan, Hong; Yang, Fei; Li, Wenbiao; Li, Tengcheng; Xie, Juncong

doi:10.1177/1744806916674479

Cited by 31 publications

(35 citation statements)

References 61 publications

(96 reference statements)

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“…In our previous studies, we observed that the activation of astrocytes and microglia contribute to mechanical allodynia in CYP-induced cystitis model [8,9]. As far as we know, Iba1 and GFAP are the main markers of microglia and astrocytes, respectively.…”

Section: Discussionmentioning

confidence: 93%

“…Our previous study demonstrated that neuroinflammation in the spinal dorsal horn (SDH) might be associated to mechanism of interstitial cystitis, and contribute to mechanical allodynia [8,9]. Neuroinflammation is a complex and well-coordinated process consisting of various glial cells in the central nervous system (CNS) and peripheral immune cells [10].…”

Section: Introductionmentioning

confidence: 99%

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

Ding

Chen

et al. 2020

J Neuroinflammation

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101

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Background: Patients 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. Methods: Systemic 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. Results: BDNF-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. Conclusions: In 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.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

Ding

Chen

et al. 2020

J Neuroinflammation

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101

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“…In addition, cyclophosphamide (CYP)‐induced chronic pain, which is thought to be a visceral neuropathic pain syndrome, may be initiated and maintained in part by neuroinflammation‐leading central sensitization . Our previous study showed that glia cell activation can contribute to allodynia in CYP‐induced cystitis by releasing proinflammatory cytokines and inducing central sensitization at the spinal cord level …”

Section: Introductionmentioning

confidence: 99%

“…3 Our previous study showed that glia cell activation can contribute to allodynia in CYP-induced cystitis by releasing proinflammatory cytokines and inducing central sensitization at the spinal cord level. 4 Various important signaling pathways modulate neuroinflammation, leading to chronic pain. Neuregulin-1 (Nrg1)-ErbB signaling may be involved in this process.…”

Section: Introductionmentioning

confidence: 99%

Neuregulin‐1‐ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide‐induced cystitis

Chen

Zhou

Ding

et al. 2019

Neurourology and Urodynamics

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Aims Central sensitization playsimportant roles in cyclophosphamide (CYP)‐induced cystitis. In addition, as a visceral pain, CYP‐induced chronic pain shares common pathophysiological mechanisms with neuropathic pain. Previous studies demonstrated that neuregulin‐1 (Nrg1)‐ErbB signaling contributes to neuropathic pain, but whether and how this signaling influences mechanical allodynia in CYP‐induced cystitis is unclear. This study aimed to determine whether and how Nrg1‐ErbB signaling modulates mechanical allodynia in a CYP‐induced cystitis rat model. Methods Systemic injection with CYP was used to establish a rat model of bladder pain syndrome/interstitial cystitis (BPS/IC). An irreversible ErbB family receptor inhibitor, PD168393, and exogenous Nrg1 were intrathecally injected to modulate Nrg1‐ErbB signaling. Mechanical allodynia in the lower abdomen was assessed with von‐Frey filaments using the up‐down method. Western blot analysis and immunofluorescence staining were used to measure the expression of Nrg1‐ErbB signaling, Iba‐1, p‐p38, and IL‐1β in the L6‐S1 spinal dorsal horn (SDH). Results We observed upregulation of Nrg1‐ErbB signaling as well as overexpression of the microglia activation markers Iba‐1 and p‐p38 and the proinflammatory factor, interleukin‐1β (IL‐1β), in the SDH of the cystitis group. Further, treatment with PD168393 attenuated mechanical allodynia in CYP‐induced cystitis and inhibited microglia activation, leading to decreased production of IL‐1β. The inhibitor PD168393 reversed the algesic effect of exogenous Nrg1 on the cystitis model. Conclusions Nrg1‐ErbB signaling may promote microglia activation, contributing to mechanical allodynia of CYP‐induced cystitis. Our study showed that modulation of Nrg1‐ErbB signaling may have therapeutic value for treating pain symptoms in BPS/IC.

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“…Diversas outras teorias também propostas incluem a ativação mastocitária (31)(32)(33) , liberação de mediadores inflamatórios (34)(35)(36) , infecção subclínica (37) , alterações neuropáticas (38,39) , autoimunidade (40) , alteração da vascularização da bexiga (41) , causas psiquiátricas (42)(43)(44) e susceptibilidade genética (45,46) . Considerando a dificuldade de diagnóstico, a ampla variedade de apresentações e a associação da CI com outras doenças, é provável que ela represente uma síndrome com múltiplos mecanismos fisiopatológicos e fatores etiológicos.…”

Section: Critérios De Exclusão Niddk Para Definição De Cistite Intersunclassified

Análise de polimorfismos de nucleotídeo único na cistite intersticial

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DedicatóriaA minha família pelos ensinamentos, pelos exemplos de vida e pelo apoio incondicional. A minha querida esposa e companheira Paula, que sempre me incentivou e tornou possível a realização deste sonho. "All our science, measured against reality, is primitive and childlike -and yet it is the most precious thing we have". Albert Einstein 1879-1955Agradecimentos Ao Professor Dr. Homero Bruschini, pela oportunidade, pela confiança, pelos inúmeros conselhos e ensinamentos que contribuíram muito para o meu crescimento pessoal e profissional. À Professora Dra. Sabrina Reis pelo carinho e pelos ensinamentos em pesquisa e genética.Aos colegas urologistas que fazem parte do grupo de Bexiga Neurogênica do HCFMUSP, aos residentes da urologia e aos funcionários da urologia por sua dedicação diária no atendimento e cuidados dos pacientes que participaram neste estudo.À equipe do LIM 55 que me acolheu com muito carinho e pelo imprescindível auxílio no aprendizado das técnicas moleculares.Às pacientes com Cistite Intersticial, motivo deste estudo. À FAPESP pelo apoio ao projeto e financiamento dos materiais. rs1800896, rs1800471, rs1800629, rs361525, rs1800497, rs6311, rs6277, rs6276, rs6313, rs2835859, rs11127292, rs2243248, rs6887695, rs3212227, rs1799971, rs12579350, rs3813034, rs6746030. A genotipagem foi realizada através da técnica de PCR em tempo real (q-PCR) e correlacionada com o diagnóstico de CI e com a intensidade dos sintomas álgicos. RESULTADOS: O alelo polimórfico (T) do SNP rs11127292 foi mais frequente nas pacientes com CI em relação ao grupo controle (p:0,01). O alelo polimórfico (T) do SNP rs6311 foi significativamente mais frequente nas pacientes com dor mais intensa (p:0,03). A frequência do alelo selvagem (A) do SNP rs1799971 foi maior em pacientes com dor leve a moderada (p:0,04 INTRODUCTION: Interstitial cystitis (IC) or painful bladder syndrome (PBS) is a chronic syndrome characterized by the presence of bladder/pelvic pain or discomfort and voiding symptoms such as urgency and increased urinary waking and night-time frequency in the absence of another identifiable cause to justify these symptoms. So far, there is no diagnostic test or marker to establish the presence of IC. Thus, the diagnosis is predominantly clinical, based on signs and symptoms and dependent on the exclusion of other urological diseases. The difficulty in the diagnosis and treatment of these patients reflects the little that is known about IC physiopathology and about the genetic background of the disease. The identification of new markers may provide a better understanding and management of the syndrome. As an attempt to identify genetic markers that may be associated with IC, we evaluated the presence of some genetic polymorphisms, single nucleotide polymorphisms (SNPs), in the DNA of patients with the diagnostic criteria of IC, and we compared their prevalence among IC patients and with a control group representative of the general population. The correlation of these polymorphisms considering IC and pain intensity ...

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Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis

Cited by 31 publications

References 61 publications

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

Neuregulin‐1‐ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide‐induced cystitis

Análise de polimorfismos de nucleotídeo único na cistite intersticial

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