Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease

• Type of Material: Article
• Authors: Maria G. Zizzo, University of Palermo; Monica Frinchi, University of Palermo; Domenico Nuzzo, Consiglio Nazionale delle Ricerche; Hyder Jinnah, Emory University; Giuseppa Mudo, University of Palermo; Daniele F. Condorelli, University of Catania; Francesco Caciagli, University of Chieti-Pescara; Renata Ciccarelli, University of Chieti-Pescara; Patrizia Di Iorio, University of Chieti-Pescara; Flavia Mule, University of Palermo; Natale Belluardo, University of Palermo; Rosa Serio, University of Palermo
• Language: English
• Date: 2018-03-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier B.V.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.autneu.2017.12.007
• Title of Journal or Parent Work: Autonomic Neuroscience: Basic and Clinical
• ISSN: 1566-0702
• Volume: 210
• Start Page: 55
• End Page: 64
• Grant/Funding Information: The work was supported in part by the National Institutes of Health in the USA (grant number R56 NS102980).; This work was supported by grants from “Fondi Finanziamento della Ricerca (FFR)”, University of Palermo.
• Keywords: Oxidative stress; Colon; DISORDER; Science & Technology; PHENOTYPE; Gastrointestinal motility; ADENOSINE; INTESTINAL MOTILITY; Life Sciences & Biomedicine; Cytokines; DOPAMINE LOSS; BASAL GANGLIA; HGprt enzyme; GENETIC MOUSE MODEL; LYMPHOCYTES; DEFICIENCY; PATHOPHYSIOLOGY; HGprt deficient mice; Lesch-Nyhan; Dopamine; Neurosciences & Neurology; Neurosciences
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology; Biology, Genetics

Abstract

Mutations in the HGPRT1 gene, which encodes hypoxanthine-guanine phosphoribosyltransferase (HGprt), housekeeping enzyme responsible for recycling purines, lead to Lesch-Nyhan disease (LND). Clinical expression of LND indicates that HGprt deficiency has adverse effects on gastrointestinal motility. Therefore, we aimed to evaluate intestinal motility in HGprt knockout mice (HGprt¯). Spontaneous and neurally evoked mechanical activity was recorded in vitro as changes in isometric tension in circular muscle strips of distal colon. HGprt¯ tissues showed a lower in amplitude spontaneous activity and atropine-sensitivity neural contraction compared to control mice. The responses to carbachol and to high KCl were reduced, demonstrating a widespread impairment of contractility. L-NAME was not able in the HGprt¯ tissues to restore the large amplitude contractile activity typical of control. In HGprt¯ colon, a reduced expression of dopaminergic D1 receptor was observed together with the loss of its tonic inhibitory activity present in control-mice. The analysis of inflammatory and oxidative stress in colonic tissue of HGprt¯ mice revealed a significant increase of lipid peroxidation associated with over production of oxygen free radicals. In conclusion, HGprt deficiency in mice is associated with a decrease in colon contractility, not dependent upon reduction of acetylcholine release from the myenteric plexus or hyperactivity of inhibitory signalling. By contrast the increased levels of oxidative stress could partially explain the reduced colon motility in HGprt¯ mice. Colonic dysmotility observed in HGprt¯ mice may mimic the gastrointestinal dysfunctions symptoms of human syndrome, providing a useful animal model to elucidate the pathophysiology of this problem in the LND.