BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity

Kashyap, Mahendra; Pore, Subrata K.; Groat, William C. de; Chermansky, Christopher; Yoshimura, Naoki; Tyagi, Pradeep

doi:10.1152/ajprenal.00386.2017

Cited by 30 publications

(31 citation statements)

References 57 publications

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“…As an important urinary neurotrophic factor, BDNF is detected to be abnormally elevated in some lower urinary tract diseases, such as overactive bladder [32], stress urinary incontinence [33], and interstitial cystitis [34]. BDNF plays a specific role in urinary frequency and urgency without affecting capacity [35].…”

Section: Discussionmentioning

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

107

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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: 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

107

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“…In addition, expression and activation of TrkB, normally present in approximately onethird of bladder sensory afferents, are also upregulated during bladder pathological conditions [155,156]. Overexpression of BDNF has been linked to bladder overactivity possibly via enhancement of prejunctional cholinergic transmission and mediation of altered gene expression, including TRPV1 and TRPA1 [157].…”

Section: Bdnf In the Urinary Bladdermentioning

confidence: 99%

Partners in Crime: NGF and BDNF in Visceral Dysfunction

Coelho

Oliveira

Antunes-Lopes

et al. 2019

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: Neurotrophins (NTs), particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), have attracted increasing attention in the context of visceral function for some years. Here, we examined the current literature and presented a thorough review of the subject. : After initial studies linking of NGF to cystitis, it is now well-established that this neurotrophin (NT) is a key modulator of bladder pathologies, including Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS. NGF is upregulated in bladder tissue and its blockade results in major improvements on urodynamic parameters and pain. Further studies expanded showed that NGF is also an intervenient in other visceral dysfunctions such as endometriosis and Irritable Bowel Syndrome (IBS). : More recently, BDNF was also shown to play an important role in the same visceral dysfunctions, suggesting that both NTs are determinant factors in visceral pathophysiological mechanisms. Manipulation of NGF and BDNF improves visceral function and reduce pain, suggesting that clinical modulation of these NTs may be important; however, much is still to be investigated before this step is taken. : Another active area of research is centered on urinary NGF and BDNF. Several studies show that both NTs can be found in the urine of patients with visceral dysfunction in much higher concentration than in healthy individuals, suggesting that they could be used as potential biomarkers. However, there are still technical difficulties to be overcome, including the lack of a large multicentre placebo-controlled studies to prove the relevance of urinary NTs as clinical biomarkers.

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“…Among the neurotrophins, past studies have shown overexpression of NGF and BDNF may lead to neuronal hyperinnervation and changes in bladder function . Another neurotrophin GAP‐43, is a key protein in neurite formation, regeneration, and plasticity .…”

Section: Discussionmentioning

confidence: 99%

“…Among the neurotrophins, past studies have shown overexpression of NGF and BDNF may lead to neuronal hyperinnervation and changes in bladder function. 16,17 Another neurotrophin GAP-43, is a key protein in neurite formation, regeneration, and plasticity. 18 GAP-43 plays an important role in neuron hypertrophy of chronic pancreatitis, and its expression in the pancreas was correlated with pain in the patients with chronic pancreatitis.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of neurotrophins and transforming growth factor‐β expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine‐associated cystitis

Jhang

Wang

Hsu

et al. 2019

Neurourology and Urodynamics

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Aims To investigate the mechanism of bladder nerve hyperplasia and fibrosis in the patients with ketamine‐associated cystitis (KC). Methods Sixteen patients with severe KC, six patients with mild KC, and five patients with localized invasive bladder cancer served as control patients. Bladder mucosa specimens were taken during the operations, and the specimens were stained for nerve growth factor (NGF) and S‐100 to evaluated nerve hyperplasia. The quantitative Western blot analysis was performed for NGF, brain‐derived neurotrophic factor (BDNF), growth‐associated protein 43 (GAP‐43), tropomyosin receptor kinase A and B (TrkA and TrkB), transforming growth factor‐β (TGF‐β), phosphorylated extracellular signal‐regulated kinases (p‐ERK), protein kinase B (p‐Akt), and glycogen synthase kinase 3β (p‐GSK‐3β). Results The results demonstrated diffuse NGF expression in KC bladder epithelium, lamina propria, and muscle. The GAP‐43, NGF, BDNF, TrkA, TGF‐β, p‐ERK, P‐AKT, and p‐GSK‐3β expression in the bladder mucosa specimens of patients with severe KC was significantly higher than in patients with mild KC and control patients. Expression of neurotrophins was significantly correlated with bladder capacity and pain. NGF and BDNF expression were significantly higher in the KC bladder specimens with strongly positive S‐100 staining. TGF‐β expression in the bladder specimens was significantly correlated with neurotrophins, p‐ERK, P‐AKT, and p‐GSK‐3β levels. Conclusion Our findings indicate upregulation of neurotrophins, TGF‐β, and activation of the cell proliferation kinases plays an important role in nerve hyperplasia and fibrosis mechanisms in severe KC bladders. The neurotrophins and TGF‐β interact as cause and effect, leading to bladder hypersensitivity and fibrosis in severe KC.

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BDNF overexpression in the bladder induces neuronal changes to mediate bladder overactivity

Cited by 30 publications

References 57 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

Partners in Crime: NGF and BDNF in Visceral Dysfunction

Upregulation of neurotrophins and transforming growth factor‐β expression in the bladder may lead to nerve hyperplasia and fibrosis in patients with severe ketamine‐associated cystitis

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