Background: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Bladder dysfunction is the common non-motor symptom of PD, most often presenting with detrusor overactivity (DO). Treatment of DO is currently limited, poorly tolerated and sometimes ineffective. Bladder responses are not only mediated by muscarinic cholinergic receptors (mAChR) but also by nicotinic cholinergic receptors (nAChR). However, nicotinic receptor subtypes and functions in the bladder are not clearly identified. Purpose: This study aimed at investigating the effect of varenicline, an alpha7 full agonist and alpha4beta2/alpha3 partial agonist, on detrusor strips in rat PD model induced by substantia nigra injection of 6-hydroxydopamine. Method: The detrusor activity was studied in an isolated organ bath system. Results: In PD group, the detrusor activity was increased, whereas varenicline decreased the DO. Conclusion: Alpha7 nAChR agonists may have therapeutic potential in treatment of bladder overactivity in PD.
References
[1]
Sakakibara, R., Tateno, F., Kishi, M., Tsuyuzaki, Y., Uchiyama, T. and Yamamoto, T. (2012) Pathophysiology of Bladder Dysfunction in Parkinson’s Disease. Neurobiology of Disease, 46, 565-571. https://doi.org/10.1016/j.nbd.2011.10.002
[2]
Araki, I. and Kuno, S. (2000) Assessment of Voiding Dysfunction in Parkinson’s Disease by the International Prostate Symptom Score. Journal of Neurology, Neurosurgery, and Psychiatry, 68, 429-433. https://doi.org/10.1136/jnnp.68.4.429
[3]
Campos-Sousa, R.N., Quagliato, E., da Silva, B.B., de Carvalho, R.M., Ribeiro, S.C. and de Carvalho, D.F. (2003) Urinary Symptoms in Parkinson’s Disease: Prevalence and Associated Factors. Arquivos de Neuro-Psiquiatria, 61, 359-363. https://doi.org/10.1590/S0004-282X2003000300007
[4]
Winge K., Skau, A.M., Stimpel, H., Nielsen, K.K. and Werdelin, L. (2006) Prevalence of Bladder Dysfunction in Parkinson’s Disease. Neurourology and Urodynamics, 25, 116-122. https://doi.org/10.1002/nau.20193
[5]
Berger, Y., Blaivas, J.G., DeLaRocha, E.R. and Salinas, J.M. (1987) Urodynamic Findings in Parkinson’s Disease. The Journal of Urology, 138, 836-838. https://doi.org/10.1016/S0022-5347(17)43390-8
[6]
Sakakibara, R., Shinotoh, H., Uchiyama, T., Sakuma, M., Kashiwado, M., Yoshiyama, M. and Hattori, T. (2001) Questionnaire-Based Assessment of Pelvic Organ Dysfunction in Parkinson’s Disease. Autonomic Neuroscience: Basic & Clinical, 92, 76-85. https://doi.org/10.1016/S1566-0702(01)00295-8
[7]
Uchiyama, T., Sakakibara, R., Hattori, T. and Yamanishi, T. (2003) Short-Term Effect of a Single Levodopa Dose on Micturition Disturbance in Parkinson’s Disease Patients with the Wearing-Off Phenomenon. Movement Disorders: Official Journal of the Movement Disorder Society, 18, 573-578. https://doi.org/10.1002/mds.10403
[8]
Wein, A.J. and Rackley, R.R. (2006) Overactive Bladder: A Better Understanding of Pathophysiology, Diagnosis and Management. The Journal of Urology, 175, S5-S10. https://doi.org/10.1016/S0022-5347(05)00313-7
[9]
Lertxundi, U., Isla, A., Solinis, M.A., Domingo-Echaburu, S., Hernandez, R., Peral-Aguirregoitia, J. and Medrano, J. (2015) Anticholinergic Burden in Parkinson’s Disease Inpatients. European Journal of Clinical Pharmacology, 71, 1271-1277. https://doi.org/10.1007/s00228-015-1919-7
[10]
Batla, A., Tayim, N., Pakzad, M. and Panicker, J.N. (2016) Treatment Options for Urogenital Dysfunction in Parkinson’s Disease. Current Treatment Options in Neurology, 18, 45. https://doi.org/10.1007/s11940-016-0427-0
[11]
Uchiyama, T. and Chess-Williams, R. (2004) Muscarinic Receptor Subtypes of the Bladder and Gastrointestinal Tract. Journal of Smooth Muscle Research = Nihon Heikatsukin Gakkai Kikanshi, 40, 237-247. https://doi.org/10.1540/jsmr.40.237
[12]
Kim, H.S., Park, W.J., Park, E.Y., Koh, J.S., Hwang, T. and Kim, J. (2015) Role of Nicotinic Acetylcholine Receptor α3 and α7 Subunits in Detrusor Overactivity Induced by Partial Bladder Outlet Obstruction in Rats. International Neurourology Journal, 19, 12-18. https://doi.org/10.5213/inj.2015.19.1.12
[13]
Beckel, J.M., Kanai, A., Lee, S.J., de Groat, W.C. and Birder, L.A. (2006) Expression of Functional Nicotinic Acetylcholine Receptors in Rat Urinary Bladder Epithelial Cells. American Journal of Physiology. Renal Physiology, 290, F103-F110. https://doi.org/10.1152/ajprenal.00098.2005
[14]
Beckel, J.M. (2009) Expression and Function of Urothelial Nicotinic Acetylcholine Receptors. Thesis, University of Pittsburgh School of Medicine, Pittsburgh, 1-193.
[15]
Mihalak, K.B., Carroll, F.I. and Luetje, C.W. (2006) Varenicline Is a Partial Agonist at alpha4beta2 and a Full Agonist at alpha7 Neuronal Nicotinic Receptors. Molecular Pharmacology, 70, 801-805. https://doi.org/10.1124/mol.106.025130
[16]
Paxinos, G. and Watson, C. (1998) The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego.
[17]
Kurosawa, T., Higuchi, K., Okura, T., Kobayashi, K., Kusuhara, H. and Deguchi, Y. (2017) Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells. Journal of Pharmaceutical Sciences, 106, 2576-2582. https://doi.org/10.1016/j.xphs.2017.04.032
[18]
Mitra, R., Aronsson, P., Winder, M., Tobin, G., Bergquist, F. and Carlsson, T. (2015) Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson’s Disease. Journal of Parkinson’s Disease, 5, 301-311. https://doi.org/10.3233/JPD-140509
[19]
Yamanishi, T., Chapple, C.R. and Chess-Williams, R. (2001) Which Muscarinic Receptor Is Important in the Bladder? World Journal of Urology, 19, 299-306. https://doi.org/10.1007/s003450100226
[20]
Ratz, P.H., Berg, K.M., Urban, N.H. and Miner, A.S. (2005) Regulation of Smooth Muscle Calcium Sensitivity: KCl as a Calcium-Sensitizing Stimulus. American Journal of Physiology-Cell Physiology, 288, C769-C783. https://doi.org/10.1152/ajpcell.00529.2004
[21]
Hawthorn, M.H., Chapple, C.R., Cock, M. and Chess-Williams, R. (2000) Urothelium-Derived Inhibitory Factor(s) Influences on Detrusor Muscle Contractility in Vitro. British Journal of Pharmacology, 129, 416-419. https://doi.org/10.1038/sj.bjp.0703068
[22]
Haberberger, R.V., Henrich, M., Lips, K.S. and Kummer, W. (2003) Nicotinic Receptor alpha 7-Subunits Are Coupled to the Stimulation of Nitric Oxide Synthase in Rat Dorsal Root Ganglion Neurons. Histochemistry and Cell Biology, 120, 173-181. https://doi.org/10.1007/s00418-003-0550-3
[23]
Antoine Taly, A., Corringer, P.J., Denis Guedin, D., Pierre Lestage, P. and Changeux, J.P. (2009) Nicotinic Receptors: Allosteric Transitions and Therapeutic Targets in the Nervous System. Nature Reviews Drug Discovery, 8, 733-750. https://doi.org/10.1038/nrd2927
[24]
Clementi, F. and Fumagalli, G. (2015) General and Molecular Pharmacology: Principles of Drug Action eBook.
[25]
Dalmose, A.L., Bjarkam, C.R., Sørensen, J.C., Djurhuus, J.C. and Jørgensen, T.M. (2004) Effects of High Frequency Deep Brain Stimulation on Urine Storage and Voiding Function in Conscious Minipigs. Neurourology and Urodynamics, 23, 265-272. https://doi.org/10.1002/nau.20026
