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Auton Neurosci. 2018 Mar;210:55-64. doi: 10.1016/j.autneu.2017.12.007. Epub 2017 Dec 20.

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

Author information

1
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; ATeN (Advanced Technologies Network Center), University of Palermo, Viale delle Scienze, Palermo, Italy.
2
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Corso Tukory 129, 90134 Palermo, Italy.
3
Institute of Biomedicine and Molecular Immunology "Alberto Monroy" (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo la Malfa, 153, 90146 Palermo, Italy.
4
Departments of Neurology, Human Genetics and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
5
Department of Bio-Medical Sciences, University of Catania, Via S. Sofia 97, 95100 Catania, Italy.
6
Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, Pal. B, 66100 Chieti, Italy.
7
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy.
8
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Corso Tukory 129, 90134 Palermo, Italy. Electronic address: natale.belluardo@unipa.it.

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.

KEYWORDS:

Colon; Cytokines; Dopamine; Gastrointestinal motility; HGprt deficient mice; HGprt enzyme; Lesch-Nyhan; Oxidative stress

PMID:
29305058
PMCID:
PMC5904834
[Available on 2019-03-01]
DOI:
10.1016/j.autneu.2017.12.007
[Indexed for MEDLINE]

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