Date of Award

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

First Advisor

Margaret A. Vizzard

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory pelvic pain syndrome characterized by urinary frequency and urgency, bladder discomfort, decreased bladder capacity, and pelvic pain. A positive feedback loop of bladder inflammation and afferent hypersensitization is currently thought to underlie IC/BPS. Inflammation increases bladder afferent excitability, which in turn releases inflammatory neuropeptides, growth factors, cytokines, and chemokines throughout the micturition pathway, leading to altered bladder function and sensation. There currently exists no effective therapy for IC/BPS.

While its etiology remains unknown, a large body of evidence suggests a role for changes in neurotrophin signaling, particularly that of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Both are increased in the urine and bladders of humans and animals with cystitis. Administration or overexpression of NGF in the bladder produces changes in bladder function consistent with cystitis; complementarily, pharmacological disruptions of both NGF and BDNF are associated with improved bladder function in models of bladder inflammation. However, severe side effects associated with anti-NGF treatment have hampered attempts to develop effective therapies, highlighting the need for additional therapeutic targets. Additionally, neurotrophin signaling is complex and has not been thoroughly characterized in the bladder.

Here, we instead target neurotrophin signaling at the receptor level. Using conscious, open-outlet cystometry, we demonstrate bladder function improvement in a mouse model of cyclophosphamide (CYP)-induced cystitis as a consequence of treatment with novel pharmacological inhibitors for the NGF receptor TrkA, the BDNF receptor TrkB, and the pan-neurotrophin receptor p75NTR. Additionally, using immunohistochemistry and enzyme-linked immunosorbent assays, we demonstrate changes in a variety of NGF signaling–related proteins (NGF, TrkA, p75NTR, p-JNK, p-ERK) as a consequence of CYP treatment, inducing cystitis, and in response to subsequent treatment with TrkA and p75NTR inhibitors. Our findings demonstrate that these receptors represent additional potent therapeutic targets in mice with cystitis and reveal additional novel therapeutic targets that may be useful in the treatment of IC/BPS and lower urinary tract symptoms in other inflammatory disorders of the bladder.

Language

en

Number of Pages

166 p.

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