Crosstalk between inflammation, voiding dysfunction, and psychiatric symptoms: novel hypothesis and therapeutics for urinary incontinence.

The lower urinary tract, composed of the urinary bladder and urethra, is responsible for urine storage and excretion, which are regulated by the peripheral nervous system, spinal cord, and brain. Whereas micturition is a voluntary behavior depending on executive control and social cognition, it is unclear how brain neural network disruption causes urinary incontinence. Data suggest that when bladder volume increases, healthy individuals experience dorsolateral prefrontal cortex activation with executive control to preserve continence, and this brain region regulates the cingulate cortex and emotional system to modulate urinary urgency and emotions. In patients with urge urinary incontinence, proinflammatory diets can induce inflammation in the lower urinary tract with voiding dysfunction and resultant increases in blood proinflammatory cytokine levels. The proinflammatory cytokines likely cause blood-cerebrospinal fluid barrier disruption, presumably accompanied by an elevation of proinflammatory cytokine concentrations in the cerebrospinal fluid, resulting in glial cell aberration-related hyperactivation of the cingulate cortex and emotional system as well as deactivation of the dorsolateral prefrontal cortex. The impaired dorsolateral prefrontal cortex regulation of these brain regions can contribute to executive control impairment with incontinence, uncontrollable urinary urgency, involuntary urination-associated anxiety, depressed mood caused by anticipatory anxiety, and catastrophizing about bladder fullness with urinary urgency due to cognitive distortion or catastrophic thinking, leading to a vicious spiral along with dysfunctional voiding. These symptoms suggest that while diet-related inflammation presumably initiates lower urinary tract dysfunction, neuroinflammation-induced brain neural network disturbance may promote the progression of urge urinary incontinence. Our model could predict novel medications for this condition. SIGNIFICANCE STATEMENT: Our hypothesis suggests that promoting anti-inflammation and/or resolution of inflammation in the brain as well as lower urinary tract may have therapeutic potential in the management of urinary incontinence with uncontrollable urinary urgency. Nonsteroidal anti-inflammatory drugs prevent cyclooxygenase activity and prostaglandin production, and prostaglandin E₂ is responsible for resolution of inflammation as well as inflammatory responses; therefore, we propose novel medications for this condition that can prompt anti-inflammatory and proresolution properties without inhibition of prostaglandin production.