Inzichten uit nieuwe diermodellen voor neurogene detrusor onderactiviteit

Detrusor underactivity (DU) is a bladder emptying disorder where a detrusor contraction of reduced strength and/or duration results in reduced urine flow, prolonged and/or incomplete bladder emptying. It is a poorly understood disease and its pathophysiology remains largely elusive. Limited therapeutic options exist for DU, focusing mainly on minimizing complications from post-void residual by bladder catheterization. The International Consultation on Incontinence Research Society requested novel preclinical and clinical research initiatives to assess the pathogenesis of the disease. In this thesis, we aimed to identify a subgroup of DU patients of interest, define an animal model for this patient group and investigate the bladder wall in the animal model. First, we identified a subgroup of DU patients of special interest (chapter 3). We performed a retrospective chart review to identify etiological risk factors in patients with DU and acontractile detrusor performing clean intermittent catheterization. Neurological conditions were the most frequently identified underlying pathology in 68% with peripheral neural injury present in 47% of patients. Seventy-five percent of patients continue to require catheterization at a follow-up of > 3 years, indicating the need for research. Based on these results, we chose an animal model of peripheral neuropathy, to study the pathophysiology of DU. Second, we hypothesized that a crush injury of the pelvic nerve in rats, containing the preganglionic parasympathetic and afferent fibers, induces an animal model for neurogenic DU. The autonomic pelvic plexus of the rat is organized around a single pelvic ganglion, the major pelvic ganglion, making it of special interest for research. We characterized the bilateral pelvic nerve crush injury (BPNI) model in chapter 4. Indeed, BPNI induces overflow incontinence shortly after injury. Subsequently, partial recovery occurs and rats exhibit decreased maximum pressures and reduced voided percentage, hallmarks of DU. We also defined a second animal model for neurogenic bladder dysfunction: the experimental autoimmune encephalitis model, a rat model for bladder dysfunction observed in multiple sclerosis (MS) (chapter 6). Bladder dysfunction was more frequent with increasing neurological severity score. Both detrusor overactivity as detrusor underactivity were observed, equally to the lower urinary tract dysfunction observed in patients with MS. Then we performed a functional and morphological exploration of the bladder wall (chapter 4 and 6). We found that the contractility of the bladder wall was maintained. Correspondingly, the contractile response to parasympathetic stimulation remained intact in both the BPNI as the EAE model. However, a functional and morphological denervation was observed in the BPNI model. These results imply that the bladder wall maintains its capability to contract in response to neural stimuli. Future research focusing on neuroprotection or neuroregeneration is therefore of special interest to improve iatrogenic neurogenic DU. Lastly, a cholinergic hypersensitivity was observed after BPNI. In chapter 5, we investigated the role of the M2 muscarinic receptor for this hypersensitivity. Although agonist experiments were suggestive of a role of M2, antagonist and molecular experiments could not confirm this and the M3 muscarinic receptor remained the most important receptor for smooth muscle activation after BPNI. Taken together, in this doctoral thesis we defined animal models for the clinical relevant group of patients with neurogenic DU. The bladder wall preserved its contractile potential. The BPNI rat model is an excellent animal model to study the pathophysiology of neurogenic DU and to test potential therapeutic strategies.