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

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.

Stress-induced symptom exacerbation: Stress increases voiding frequency, somatic sensitivity, and urinary bladder inflammation when combined with low concentration cyclophosphamide treatment in mice

“…We also demonstrated increased expression of inflammatory mediators in the urinary bladder including neurotrophic factors (e.g., NGF, BDNF), chemokines (CXC) and IL-6 expression in the urinary bladder consistent with a large body of literature demonstrating roles for inflammatory mediators in preclinical animal models of and in IC/BPS patients (18,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Urinary bladder neurotrophic factor (i.e., NGF, BDNF), CXCL9, CXCL10 and IL-6 expression was increased in mice with CYP alone, RVS alone and CYP+RVS compared to control mice.…”

“…Animal Care was under the supervision of the UVM Office of Animal Care Management in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and National Institutes of Health (NIH) guidelines. We used female mice because of the female predominance of IC/BPS (24,35,36). Estrous cycle status was not determined for mice in these studies.…”

“…In this paper, we describe our characterization of the SISE model including, bladder function with conscious, open outlet continuous cystometry and somatic sensitivity with von Frey filament testing. We have also examined corticosterone expression, and expression of inflammatory mediators including neurotrophic factor (NGF, BDNF) (18)(19)(20), chemokine (CXC) and interleukin-6 (IL-6) (18,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) expression in the urinary bladder. These initial results demonstrated that CYP alone, or RVS alone creates a change in the inflammatory environment of the urinary bladder and a systemic increase in corticosterone expression but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS).…”

HO-1 alleviates neuroinflammation and cystitis-related symptoms in cyclophosphamide-induced cystitis via the SIRT1 pathway

“…We used CYP (Sigma-Aldrich, St. Louis, MO, USA) to establish the cystitis model, as previously described [34,35]. Brie y, rats received intraperitoneal (i.p.)…”