Neurobiological insights into lower urinary tract dysfunction: evaluating the role of brain-derived neurotrophic factor

Abstract

Lower urinary tract dysfunction (LUTD) encompasses a range of debilitating conditions that affect both sexes and different age groups. Understanding the underlying neurobiological mechanisms contributing to LUTD has emerged as a critical avenue for the development of targeted therapeutic strategies. Brain-derived neurotrophic factor (BDNF), a prominent member of the neurotrophin family, has attracted attention due to its multiple roles in neural development, plasticity, and maintenance. This review examines the intricate interplay between neurobiological factors and LUTD, focusing on the central involvement of BDNF. The review emphasizes the bidirectional relationship between LUTD and BDNF and explores how LUTD-induced neural changes may affect BDNF dynamics and vice versa. Growth factor therapy and the combined administration of controlled release growth factors and stem cells are minimally invasive treatment strategies for neuromuscular injury. Among the many growth factors and cytokines, brain-derived neurotrophic factor (BDNF) plays a prominent role in neuromuscular repair. As an essential neurotrophin, BDNF is involved in the modulation of neuromuscular regeneration through tropomyosin receptor kinase B (TrkB). Increasing BDNF levels facilitates the regeneration of the external urethral sphincter and contributes to the regulation of bladder contraction. Treatments targeting the BDNF pathway and sustained release of BDNF may become novel treatment options for urinary incontinence and other forms of lower urinary tract dysfunction. This review discusses the applications of BDNF and the theoretical basis for its use in the treatment of lower urinary tract dysfunction, including urinary incontinence (UI), overactive bladder (OAB), and benign prostatic hyperplasia (BPH), and in the clinical diagnosis of bladder dysfunction.

Keywords: Brain-derived neurotrophic factor; benign prostatic hyperplasia; overactive bladder; pelvic muscle; pudendal nerve regeneration; sphincter function; urinary incontinence; voiding dysfunction.

Figure 1

Pathway and regulation of BDNF. A. Schematic diagram of the effects of BDNF. BDNF binds to the extracellular domain of the Trk-B receptor, activating an intracellular signaling cascade that includes the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, Ras-mitogen-activated protein kinase (MAPK) pathway, Janus kinase/signal transducer (JAK/STAT) signaling pathway and the phospholipase Cγ (PLCγ)-Ca²⁺ pathway. The effects of BDNF included neruo-genesis, vascularization, immune-regulation, redox effects, anti-apoptosis, and anti-fibrosis. B. Central mechanisms involved in neurotrophin and urinary tract regulation. Upon retrograde transport of neurotrophin along afferent fibers from the urinary tract, dorsal root ganglion neurons increase synthesis of excitatory neuromediators, such as BDNF and voltage-gated ion channels, and these neuromodulators transported anterogradely to primary afferent terminals in the spinal cord.

Figure 2

Sustained release of BDNF in vivo. A. BDNF can be carried by microbeads. PLGA has been widely used in crosslinking with BDNF to produce microbeads. B. Electrospun nanofibrous containing BDNF can be packaged in nanoparticles. Nanoparticles containing BDNF can achieve sustained release in target regions. C. BDNF gene can be transfected and injected into the target tissues to induce BDNF expression.

Figure 3

Role of BDNF in urinary function regulation. BDNF has promising effects on all types of neural structures such as peripheral nerves and neuromuscular junctions. The regeneration of these neural structures helps to promote functional regeneration of the bladder, sphincter and pelvic muscles.