Brain-derived neurotrophic factor in urinary continence and incontinence

Abstract

Urinary incontinence adversely affects quality of life and results in an increased financial burden for the elderly. Accumulating evidence suggests a connection between neurotrophins, such as brain-derived neurotrophic factor (BDNF), and lower urinary tract function, particularly with regard to normal physiological function and the pathophysiological mechanisms of stress urinary incontinence (SUI) and bladder pain syndrome/interstitial cystitis (BPS/IC). The interaction between BDNF and glutamate receptors affects both bladder and external urethral sphincter function during micturition. Clinical findings indicate reduced BDNF levels in antepartum and postpartum women, potentially correlating with postpartum SUI. Experiments with animal models demonstrate that BDNF is decreased after simulated childbirth injury, thereby impeding the recovery of injured nerves and the restoration of continence. Treatment with exogenous BDNF facilitates neural recovery and the restoration of continence. Serotonin and noradrenaline reuptake inhibitors, used to treat both depression and SUI, result in enhanced BDNF levels. Understanding the neurophysiological roles of BDNF in maintaining normal urinary function and in the pathogenesis of SUI and BPS/IC could lead to future therapies based on these mechanisms.

Figure 1 |

The neuromodulatory effects of BDNF in the dorsal root ganglion, in relation to lower urinary tract function. BDNF expression is mediated by the NGF-dependent PI3K–Akt pathway. Expression of NMDA and AMPA receptors is regulated by the Ras–MAPK pathway, and modulated by BDNF–Trk-B signalling. Abbreviations: Akt, protein kinase B; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; PDK, phosphoinositide-dependent kinase; PI3K, phosphatidylinositol 3-kinase; Ras, Ras small GTPase family proteins; Trk, tropomyosin-related kinase.

Figure 2 |

Schematic diagram of the interaction between BDNF and glutamate receptors. BDNF binds to the extracellular domain of Trk-B receptor, activating an intracellular signalling cascade that includes PI3K–Akt, Ras–MAPK and the PLCγ–Ca²⁺ pathways. a | BDNF can facilitate NMDA receptor and AMPA receptor signalling through Fyn and PLCγ-Ca²⁺ and CaMKII pathways. NMDA and AMPA receptor expression is enhanced through the BDNF-mediated MAPK pathway. b | Glutamate receptors modulate BDNF signalling through Lyn and calcium signalling, which further induces BDNF expression and secretion in an autocrine fashion. Abbreviations: Akt, protein kinase B; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; CaMKII, calcium/calmodulin-dependent protein kinase II; CREB, cAMP-responsive element-binding protein; DAG, diacylglycerol; EGR3, early growth response protein 3; ERK, extracellular signal-regulated kinase; Fyn, tyrosine-protein kinase Fyn; IP₃, inositol trisphosphate; Lyn, tyrosine-protein kinase Lyn; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; NmDA, N-methyl-D-aspartate; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLCγ, phospholipase Cγ; Ras, Ras small GTPase family proteins; Trk-B, tropomyosin-related kinase B; TRPC3, short transient receptor potential channel 3; VGCC, voltage-gated calcium channel.

Figure 3 |

BDNF regulation of lower urinary tract function. BDNF facilitates PN function and could increase EUS muscle tone (1). Retrograde transport of BDNF from the bladder to the DRG has a role in DOA (2). BDNF-mediated glutamate signalling participates in bladder and EUS contractility (3). Duloxetine promotes BDNF expression and has a critical role in maintaining continence (4). The mechanism of duloxetine in treating overactive bladder is to promote the sympathetic storage reflex and increase bladder capacity during urine storage (5). Abbreviations: BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; DOA, detrusor overactivity; DRG, dorsal root ganglion; EUS, external urethral sphincter; NGF, nerve growth factor; PN, pudendal nerve; PNS, peripheral nervous system; SUI, stress urinary incontinence; Trk-A, tropomyosin-related kinase A.