Traumatic brain injury (TBI), aside from affecting motor, cognitive, and behavioral function, is also associated with disorders of the autonomic nervous system. Patients that experience TBI often suffer from lower urinary tract symptoms such as bladder overactivity, urge incontinence, detrusor underactivity, and urinary retention. Although several factors have been implicated in the development of TBI-induced bladder dysfunction, the exact mechanism underling these pathophysiological changes has not been elucidated. High levels of oxidative stress and an imbalance between the antioxidant system and reactive oxygen species have been demonstrated after TBI [1]. Moreover, the inflammatory response is believed to contribute significantly to the clinical and functional outcomes of TBI [2]. Thioredoxin-interacting protein (TXNIP), is a widely expressed protein that plays an important role in the stress response pathway in several tissue and organs by inhibiting the antioxidant function of thioredoxin. Additionally, TXNIP functions as a regulator of the inflammatory-response pathway by interacting with NLRP3 and leading to the formation of the of NLRP3 inflammasome. Recent studies have shown that TXNIP expression in the central nervous system increases with TBI [3]. Therefore, the aim of this study was to investigate the contribution of oxidative stress and inflammation on TBI-induced bladder dysfunction in mice with genetic deletion of TXNIP.

Both male and female TXNIP-KO mice and age-matched WT mice were subjected to standardized focal TBI under anesthesia using a device that produced a frontal impact. A similar procedure but with the omission of the final impact was used to obtain sham control mice from each gender and genotype. Acute and chronic changes in detrusor contractility were assessed after 24 hours and 8 weeks post-TBI by myography (n ≥ 8 in each group and sex). Mucosa-intact bladder tissue was mounted in organ baths under physiologic conditions and stimulated with purinergic and cholinergic receptor agonists. Additionally, neurogenic responses were elicited by electrical field stimulation (EFS, 1-64Hz, 30V, 10sec) delivered by platinum electrodes parallel to the muscle tissue. Dose and frequency response curves were generated in male and female mice and compared between sham and TBI in both TXNIP-KO and WT mice. In addition, purinergic (P2X1) and muscarinic (M3, M2) receptor expression levels were determined by real time PCR in in bladders from each group in the acute stage. Differences among groups and conditions were statistically detected using one-way analysis of variance.

After 24-hours of TBI, bladder contractions in response to exogenous administration of physiologic agonists were not different from sham in both WT and TXNIP-KO mice from both genders. In contrast, compared with their respective sham animals, the amplitude of neurogenic BSM contractions induced by EFS were significantly higher in TBI mice; in females, the TBI-induced increase in neurogenic contractions was limited to the low-middle frequencies of stimulation, while in male, TBI affected predominantly the higher frequencies. However, in both male and female TXNIP-KO mice, bladder contractility after acute injury was not different from uninjured sham mice.  No increases in purinergic or muscarinic receptor expression were detected among these groups and/or genders.  After 8 weeks, bladder contractility in both WT and TXNIP-KO mice with TBI was similar to sham mice.

Moderate TBI causes immediate systemic effects that directly impact bladder function.  The acute neurogenic bladder hypercontractility induced by TBI was prevented by TXNIP deletion, indicating that increased oxidative stress and inflammation underlie these alterations in contractility. However, the TBI-induced bladder hypercontractility resolves in the chronic stage of injury.

The inflammatory/oxidative stress pathways may potentially represent a new therapeutic target for the management of acute LUTS associated with TBI.

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JAMA Neurol. 72(3):355-62; 2015.
Antioxid Redox Signal.;38(4-6):425-441; 2023.