Blebbistatin, a Myosin II Inhibitor, Exerts Antidepressant-Like Activity and Suppresses Detrusor Overactivity in an Animal Model of Depression Coexisting with Overactive Bladder

Andrzej Wróbel,Małgorzata Bańczerowska-Górska,Urszula Doboszewska,Ewa Poleszak,Paweł Miotła,Tomasz Rechberger,Edyta Wlaźlak,Jarosław Dudka,Piotr Czuczwar,Ewa Rechberger,Piotr Wlaź

doi:10.1007/s12640-018-9948-5

Abstract

Overactive bladder (OAB) coexists with depression in women. Here, we assessed the effects of a 1-week treatment with blebbistatin, a myosin II inhibitor, on changes in behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA), with the aid of the forced swim test (FST), spontaneous locomotor activity test, and in vivo cystometric investigations in female Wistar rats. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased corticotropin-releasing factor (CRF) level in the plasma, prefrontal cortex (PFC), hippocampus (Hp), Barrington’s nucleus (BN), and urinary bladder. Moreover, 13-cis-RA decreased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in plasma, PFC, Hp, and BN, while it increased BDNF and NGF levels in urinary bladder. Blebbistatin exerted antidepressant-like effect and attenuated changes in the cystometric parameters as well as the central and peripheral levels of CRF, BDNF, and NGF that were induced by 13-cis-RA, while it did not affect urine production, mean, systolic or diastolic blood pressure, or heart rate. The results point to blebbistatin as a potential treatment option for OAB coexisting with depression.

Highlights

Overactive bladder (OAB) is a widely prevalent syndrome characterized by urinary urgency with or without urge incontinence, usually with frequency and nocturia (Haylen et al 2012), which is more common in women than in men before the age of 60 years (Irwin et al 2011)
We have demonstrated that antimuscarinic drugs—representatives of first- and secondline treatments for OAB as well as a representative of proposed novel treatments for OAB—a reversible CRF1 antagonist, SN003, attenuated detrusor overactivity (DO) symptoms induced by 13-cis-RA (Wróbel and Rechberger 2016)
The obtained results point to BLEB as a potential treatment strategy for OAB coexisting with depression, possibly with favorable cardiovascular profile

Summary

Introduction

Overactive bladder (OAB) is a widely prevalent syndrome characterized by urinary urgency with or without urge incontinence, usually with frequency and nocturia (Haylen et al 2012), which is more common in women than in men before the age of 60 years (Irwin et al 2011). Because there is no gold standard for the treatment of these coexisting conditions, therapeutic agents that target both OAB and depression are necessary. A precipitant of depression (Gold et al 2015), activates the LC through efferents from the corticotropin-releasing factor (CRF) system (Chandley and Ordway 2012). In addition to CRF, neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) may be involved in the pathophysiology underlying OAB coexisting with depression (Cruz 2014; Steers 2002). Neurotrophins may induce plastic changes of the neuronal circuits that govern bladder function (Ochodnicky et al 2012). Elevated levels of NGF and BDNF were found in the bladder in animal models of OAB and in humans with OAB symptoms (Cruz 2014; Kashyap et al 2018)

Methods

Results

Discussion

Conclusion