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The Orexin OX2 Receptor-Dependent Pathway Is Implicated in the Development of Overactive Bladder and Depression in
Anna Serefko1, Jan Wróbel2, Aleksandra Szopa1
1Department of Clinical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland.
Aim:
In the present study, we wanted to check whether TCS OX2 29 (TCS), a potent selective antagonist of OX2 receptors, would have positive effects in an animal model of detrusor overactivity co-existed with the depression-like state in Wistar male rats.
Methods:
The forced swim test with the measurement of spontaneous locomotor activity, conscious cystometry, determination of c-Fos expression in central micturition areas, and a set of biochemical analyses (with the use of urine, hippocampus, bladder urothelium, and detrusor muscle of tested animals) were carried out.
Results:
The outcomes showed that a 7-day administration of TCS (3 mg/kg/day, subcutaneously) normalizes the cystometric parameters corresponding to overactivity of the detrusor and reverses the pro-depressive response. Furthermore, the antagonism of OX2 receptors restored the abnormal levels of overactive bladder markers (i.e., ATP, CGRP, OCT3, TRPV1, ROCK1, and VAChT), diminished neuronal overactivity in central micturition areas (i.e., pontine micturition center, ventrolateral periaqueductal gray, and medial preoptic area) as well as restored the altered hippocampal levels of CRF, cytokines (IL-1β, IL-6, IL-10, and TNF-α), and growth factors (BDNF and NGF) that reflected biochemical disturbances detected in depressed people.
Conclusions:
It seems that our findings open new perspectives regarding the implication of the orexin system in the functioning of the urinary bladder and in the pathophysiology of depression.
Insights
TCS OX2 29 (TCS) treatment in rats improved bladder overactivity and depression-like symptoms by targeting OX2 receptors. This suggests the orexin system
Area of Science:
- Neuroscience
- Urology
- Pharmacology
Background:
- Detrusor overactivity and depression-like states often co-occur.
- The orexin system's role in these conditions is not fully understood.
- TCS OX2 29 (TCS) is a selective OX2 receptor antagonist.
Purpose of the Study:
- To investigate the therapeutic potential of TCS OX2 29 (TCS) in a rat model.
- To assess TCS effects on co-existing detrusor overactivity and depression-like behaviors.
- To explore the involvement of the orexin system in urinary bladder function and depression.
Main Methods:
- Utilized the forced swim test to evaluate depression-like responses.
- Conscious cystometry was performed to assess bladder function.
- Measured c-Fos expression in central micturition areas and conducted biochemical analyses of urine, hippocampus, bladder urothelium, and detrusor muscle.
Main Results:
- Seven-day TCS administration (3 mg/kg/day) normalized cystometric parameters and reversed depression-like behaviors.
- TCS treatment restored abnormal levels of key markers associated with overactive bladder and depression.
- Neuronal activity in central micturition areas and altered hippocampal levels of CRF, cytokines, and growth factors were normalized by TCS.
Conclusions:
- The orexin system plays a significant role in urinary bladder function.
- OX2 receptor antagonism shows promise for treating co-existing detrusor overactivity and depression.
- These findings open new avenues for understanding the pathophysiology of both conditions.
