Animal Model for Lower Urinary Tract Dysfunction in Parkinson's Disease

Abstract

Although Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and subsequent motor symptoms, various non-motor symptoms often precede these other symptoms. While motor symptoms are certainly burdensome, a wide range of non-motor symptoms have emerged as the key determinant of the quality of life in PD patients. The prevalence of lower urinary tract symptoms differs according to the study, with ranges between 27% and 63.9%. These can be influenced by the stage of disease, the presence of lower urinary tract-related comorbidities, and parallels with other manifestations of autonomic dysfunction. Animal models can provide a platform for investigating the mechanisms of PD-related dysfunction and for the assessment of novel treatment strategies. Animal research efforts have been primarily focused on PD motor signs and symptoms. However, the etiology of lower urinary tract dysfunction in PD has yet to be definitively clarified. Several animal PD models are available, each of which has a different effect on the autonomic nervous system. In this article, we review the various lower urinary tract dysfunction animal PD models. We additionally discuss techniques for determining the appropriate model for evaluating the development of lower urinary tract dysfunction treatments.

Keywords: Parkinson’s disease; animal model; detrusor overactivity; lower urinary tract dysfunction; non-motor symptom; overactive bladder.

Figure 1

Cystometry parameters. Typical cystometric chart in rats. [10].

Figure 2

Urethral pressure amplitude during electrical stimulation (A-URE) and urethral baseline pressure (UBP). The urethral baseline pressure (UBP) was defined as the flat section of the pressure recording that is seen just before the response to the electrical stimulation. The amplitude during the electrical stimulation (A-URE) was defined as the average value of the maximal urethral pressure change from the UBP when electrical stimulations were given to cause pressure changes from the UBP [19].

Figure 3

Working model of bladder dysfunction in PD. A hypothetical diagram demonstrates a working model of bladder dysfunction in PD. Micturition reflex is controlled by spinobulbospinal pathways through PAG in the midbrain and PMC in the brainstem. This neural circuit is under the control of higher centers, including the anterior cingulate cortex (ACC) and other cortex regions. (Intact) Under normal conditions, tonic inhibition from ACC suppresses the micturition reflex. Tonic firing (+) of dopaminergic neurons in the substantia nigra pars compacta (SN) activates the dopamine D1 receptors expressed on GABAergic inhibitory neurons in the striatum to induce tonic GABAergic inhibition (−) of the micturition reflex at the level of PAG. At the same time, D1 receptor stimulation suppresses the activity of adenosinergic neurons, which exert an excitatory effect on micturition via adenosine A2A receptors (+). (Parkinson‘s disease) In PD, dopaminergic neurons in the SN are lost (lesion), leading to the loss of dopamine D1 receptors activation (D1 (loss of activation)), which results in reduced activation inhibitory GABAergic neurons in the striatum (GABA (loss of inhibition)). At the same time, reduced D1 receptor stimulation enhances the adenosinergic mechanism to stimulate adenosine A2A receptors (A2A stimulation (++)), leading to facilitation of the spinobulbospinal pathway controlling the micturition reflex pathway. Administration of dopamine D1 receptor agonist (SKF 38393) can restore the GABAergic nerve activity and suppress A2A receptor-mediated activation to reduce bladder overactivity in PD. Furthermore, administration of adenosine A2A antagonists (ZM241385 or istradefylline) can suppress A2A receptor-mediated activation of the micturition reflex to reduce bladder overactivity in PD. Dopamine D2 receptors (D2 (+)) expressed in the spinal cord enhances the micturition reflex.

Figure 4

Working model for urethral dysfunction in PD. Schematic of our working model for urethral dysfunction. The active urethral closure mechanisms are regulated by the spinobulbospinal pathway. Intact: Descending signals of serotonergic and noradrenergic pathways from neurons in the raphe nucleus (RN) and locus coeruleus (LC), respectively. This neural circuit is under the control of the supraspinal regions and maintains urethral closure mechanisms. The descending signals travel downward to Onuf’s nucleus to innervate the external urethral sphincter and the pelvic floor muscle. Therefore, this neural system maintains active urethral closure mechanisms in the presence of increased inter-abdominal pressure. Under intact conditions, tonic inhibition (–) from supra-mesaticephalic sites suppresses bladder overactivity (+) and enhances urethral pressure (–). Parkinson‘s disease: PD dopaminergic neurons in the substantia nigra pars compacta (SN) are lost, and excitation (+) from the striatum is, therefore, decreased, leading to loss of the inhibitory functions of supra-mesaticephalic sites, including those of the cortex and supplementary motor areas (SMA). The loss of control results in facilitation of bladder overactivity (+) and inhibition of active urethral responses against increased intraabdominal pressure (–). 5-HT, 5-hydroxytryptamine; NE, norepinephrine; PAG, periaqueductal grey; PMC, pontine micturition center.