Top

Published in:

01-12-2020 | Cystitis | Research

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

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

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

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.

Hanno PM, Burks DA, Clemens JQ, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J. Urol. 2011;185(6):2162–70.PubMedCrossRef

Shie JH, Kuo HC. Higher levels of cell apoptosis and abnormal Ecadherin expression in the urothelium are associated with inflammation in patients with interstitial cystitis/painful bladder syndrome. BJU Int. 2011;108(2 Pt 2):E136–41.PubMedCrossRef

Homma Y, Ueda T, Tomoe H, Lin AT, Kuo HC, et al. Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome. Int J Urol. 2009;16(7):597–615.PubMedCrossRef

Konkle KS, Berry SH, Elliott MN, et al. Comparison of an interstitial cystitis/bladder pain syndrome clinical cohort with symptomatic community women from the RAND Interstitial Cystitis Epidemiology study. J Urol. 2012;187(2):508–12.PubMedCrossRef

Suskind AM, et al. The prevalence and overlap of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome in men: results of the RAND Interstitial Cystitis Epidemiology male study. J Urol. 2013;189(1):141–5.PubMedCrossRef

Rovner ES, Wein AJ. Incidence and prevalence of overactive bladder. Curr Urol Rep. 2002;3(6):434–8.PubMedCrossRef

Malde S, Palmisani S, Al-Kaisy A, Sahai A. Guideline of guidelines: bladder pain syndrome. BJU Int. 2018;122(5):729–43.PubMedCrossRef

Liu B, Su M, Tang S, et al. Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis. Mol Pain. 2016;15:12.

Chen JL, Zhou X, Ding HL, et al. Neuregulin-1-ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide-induced cystitis. Neurourol Urodyn. 2019;38(5):1250–60.PubMedCrossRef

10.

Yang QQ, Zhou JW. Neuroinflammation in the central nervous system: Symphony of glial cells. Glia. 2019;67(6):1017–35.PubMedCrossRef

11.

Lin YT, Ro LS, Wang HL, Chen JC. Up-regulation of dorsal root ganglia BDNF and TrkB receptor in inflammatory pain: an in vivo and in vitro study. J Neuroinflammation. 2011;8:126.PubMedPubMedCentralCrossRef

12.

Lima Giacobbo B, Doorduin J, Klein HC, et al. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Mol Neurobiol. 2019;56(5):3295–312.PubMedCrossRef

13.

Lee JY, Choi DC, Oh TH, Yune TY. Analgesic effect of acupuncture is mediated via inhibition of JNK activation in astrocytes after spinal cord injury. PLoS One. 2013;8(9):e73948.PubMedPubMedCentralCrossRef

14.

Moon J, Roh D, Yoon S, et al. σ1 receptors activate astrocytes via p38 MAPK phosphorylation leading to the development of mechanical allodynia in a mouse model of neuropathic pain. Br J Pharmacol. 2014;171(24):5881–97.PubMedPubMedCentralCrossRef

15.

Ji RR, Nackley A, Huh Y, et al. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129(2):343–66.PubMedCrossRef

16.

Luo H, Xiang Y, Qu X, et al. Apelin-13 suppresses neuroinflammation against cognitive deficit in a streptozotocin-induced rat model of Alzheimer's disease through activation of BDNF-TrkB signaling pathway. Front Pharmacol. 2019;10:395.PubMedPubMedCentralCrossRef

17.

Wei P, Zheng Q, Liu H, et al. Nicotine-induced neuroprotection against cognitive dysfunction after partial hepatectomy involves activation of BDNF/TrkB signaling pathway and inhibition of NF-κB signaling pathway in aged rats. Nicotine Tob Res. 2018;20(4):515–22.PubMedCrossRef

18.

White AO, Kramár EA, López AJ, et al. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens. Nat Commun. 2016;7:11725.PubMedPubMedCentralCrossRef

19.

Merighi A, Salio C, Ghirri A, et al. BDNF as a pain modulator. Prog Neurobiol. 2008;85(3):297–317.PubMedCrossRef

20.

Thibault K, Lin WK, Rancillac A, et al. BDNF-dependent plasticity induced by peripheral inflammation in the primary sensory and the cingulate cortex triggers cold allodynia and reveals a major role for endogenous BDNF as a tuner of the affective aspect of Pain. J Neurosci. 2014;34:14739–51.PubMedPubMedCentralCrossRef

21.

Park H, Poo M. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14(1):7–23.PubMedCrossRef

22.

Zhang L, Wang G, Ma J, et al. Brain-derived neurotrophic factor (BDNF) in the rostral anterior cingulate cortex (rACC) contributes to neuropathic spontaneous pain-related aversion via NR2B receptors. Brain Res Bull. 2016;127:56–65.PubMedCrossRef

23.

Zhou LJ, Yang T, Wei X, et al. Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain Behav Immun. 2011;25(2):322–34.PubMedCrossRef

24.

Vassoler FM, White SL, Schmidt HD, et al. Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci. 2013;16(1):42–7.PubMedCrossRef

25.

Fang X, Yang C, Li S, et al. Brain-derived neurotrophic factor-TrkB signaling in the medial prefrontal cortex plays a role in the anhedonia-like phenotype after spared nerve injury. Eur Arch Psychiatry Clin Neurosci. 2018.

26.

Miletic G, Miletic V. Loose ligation of the sciatic nerve is associated with TrkB receptor-dependent decreases in KCC2 protein levels in the ipsilateral spinal dorsal horn. Pain. 2008;137(3):532–9.PubMedCrossRef

27.

Constandil L, Aguilera R, Goich M, et al. Involvement of spinal cord BDNF in the generation and maintenance of chronic neuropathic pain in rats. Brain Res Bull. 2011;86(5-6):454–9.PubMedCrossRef

28.

Marcos JL, Galleguillos D, Pelissier T, et al. Role of the spinal TrkB-NMDA receptor link in the BDNF-induced long-lasting mechanical hyperalgesia in the rat: A behavioural study. Eur J Pain. 2017;21(10):1688–96.PubMedCrossRef

29.

Schwartz ES, Kim HY, Wang J, et al. Persistent pain is dependent on spinal mitochondrial antioxidant levels. J Neurosci. 2009;29(1):159–68.PubMedPubMedCentralCrossRef

30.

Lee UJ, Ackerman AL, Wu A, et al. Chronic psychological stress in high-anxiety rats induces sustained bladder hyperalgesia. Physiol Behav. 2015;139:541–8.PubMedCrossRef

31.

Bon K, Lichtensteiger CA, Wilson SG, Mogil JS. Characterization of cyclophosphamide cystitis, a model of visceral and referred pain, in the mouse: species and strain differences. J Urol. 2003;170(3):1008–12.PubMedCrossRef

32.

Kashyap MP, Pore SK, de Groat WC, et al. BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity. Am J Physiol Renal Physiol. 2018;315(1):F45–56.PubMedCrossRef

33.

Song QX, Chermansky CJ, Birder LA, et al. Brain derived neurotrophic factor in urinary continence and incontinence. Nat Rev Urol. 2014;11(10):579–88.PubMedPubMedCentralCrossRef

34.

Murray E, Malley SE, Qiao LY, et al. Cyclophosphamide induced cystitis alters neurotrophin and receptor tyrosine kinase expression in pelvic ganglia and bladder. J Urol. 2004;172(6 Pt 1):2434–9.PubMedCrossRef

35.

Frias B, Santos J, Morgado M, et al. The role of brain-derived neurotrophic factor (BDNF) in the development of neurogenic detrusor overactivity (NDO). J Neurosci. 2015;35(5):2146–60.PubMedPubMedCentralCrossRef

36.

Frias B, Allen S, Dawbarn D, et al. Brain-derived neurotrophic factor, acting at the spinal cord level, participates in bladder hyperactivity and referred pain during chronic bladder inflammation. Neuroscience. 2013;234:88–102.PubMedCrossRef

37.

Rexed B. A cytoanchitectonic atlas of the spinal cord in the cat. J Comp Neurol. 1954;100(2):297–379.PubMedCrossRef

38.

Steiner TJ, Turner LM. Cytoarchitecture of the rat spinal cord. J Physiol. 1972;222(2):123P–5P.PubMed

39.

Cazorla M, Prémont J, Mann A, et al. Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice. J Clin Invest. 2011;121(5):1846–57.PubMedPubMedCentralCrossRef

40.

Davis PD, Hill CH, Lawton G, et al. Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992;35(1):177–84.PubMedCrossRef

41.

Koizumi S, Contreras ML, Matsuda Y, et al. K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells. J Neurosci. 1988;8(2):715–21.PubMedPubMedCentralCrossRef

42.

Ahmed Z, Shaw G, Sharma VP, et al. Actin-binding proteins coronin-1a and IBA-1 are effective microglial markers for immunohistochemistry. J Histochem Cytochem. 2007;55(7):687–700 Epub 2007 Mar 6.PubMedCrossRef

43.

Garrison CJ, Dougherty PM, Kajander KC, Carlton SM. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 1991;565:1–7.PubMedCrossRef

44.

Gao YJ, Ji RR. Targeting astrocytes signaling for chronic pain. Neurotherapeutics. 2010;7:482–93.PubMedPubMedCentralCrossRef

45.

Robinson CR, Zhang H, Dougherty PM. Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience. 2014;274:308–17.PubMedCrossRef

46.

Zhang H, Yoon SY, Zhang H, Dougherty PM. Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of Paclitaxel-induced painful neuropathy. J Pain. 2012;13:293–303.PubMedPubMedCentralCrossRef

47.

Kirkley KS, Popichak KA, Afzali MF, et al. Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. J Neuroinflammation. 2017;14(1):99.PubMedPubMedCentralCrossRef

48.

Pekkari K, Goodarzi MT, Scheynius A, et al. Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK. Blood. 2005;105(4):1598–605.PubMedCrossRef

49.

Lin CY, Chang SL, Fong YC, et al. Apoptosis signal-regulating kinase 1 is involved in brain-derived neurotrophic factor (BDNF)-enhanced cell motility and matrix metalloproteinase 1 expression in human chondrosarcoma cells. Int J Mol Sci. 2013;14(8):15459–78.PubMedPubMedCentralCrossRef

50.

Malcangio M, Lessmann V. A common thread for pain and memory synapses? Brain-derived neurotrophic factor and trkB receptors. Trends Pharmacol Sci. 2003;24(3):116–21.PubMedCrossRef

51.

Liu M, Kay JC, Shen S, Qiao LY. Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLCγ, PKC, and PI3K/Akt pathways during colitis. J Neuroinflammation. 2015;12:151.PubMedPubMedCentralCrossRef

52.

Hildebrand ME, Xu J, Dedek A, et al. Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Rep. 2016;17(10):2753–65.PubMedCrossRef

53.

Gomes C, Ferreira R, George J, et al. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia. J Neuroinflammation. 2013;10:16.PubMedPubMedCentralCrossRef

54.

Liu SH, Lai YL, Chen BL, et al. Ultrasound enhances the expression of brain-derived neurotrophic factor in astrocyte through activation of TrkB-Akt and calcium-CaMK signaling pathways. Cereb Cortex. 2017;27(6):3152–60.PubMed

55.

Biggs JE, Lu VB, Stebbing MJ, et al. Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain. 2010;6:44.PubMedPubMedCentralCrossRef

56.

Ewa BI, Anke VS, Agnieszka B. Tumor necrosis factor-α increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner. Neuroscience. 2011;180:322–33.CrossRef

57.

Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39:3–18.PubMedCrossRef

Title: BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis
Authors: Honglu Ding
Jialiang Chen
Minzhi Su
Zhijun Lin
Hailun Zhan
Fei Yang
Wenbiao Li
Juncong Xie
Yong Huang
Xianguo Liu
Bolong Liu
Xiangfu Zhou
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Cystitis
Cystitis
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-1704-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Catastrophic consequences: can the feline parasite Toxoplasma gondii prompt the purrfect neuroinflammatory storm following traumatic brain injury?

Embryonic microglia influence developing hypothalamic glial populations

Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition

Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke