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

Flavia Mule', Rosa Maria Serio, Natale Belluardo, Giuseppa Mudo', Maria Grazia Zizzo, Domenico Nuzzo, Daniele F. Condorelli, Francesco Caciagli, Hyder A. Jinnah, Patrizia Di Iorio, Renata Ciccarelli, Domenico Nuzzo, Monica Frinchi

Risultato della ricerca: Article

2 Citazioni (Scopus)

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.
Lingua originaleEnglish
Numero di pagine10
RivistaAUTONOMIC NEUROSCIENCE: BASIC & CLINICAL
Stato di pubblicazionePublished - 2018

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Lesch-Nyhan Syndrome
Hypoxanthine Phosphoribosyltransferase
Gastrointestinal Motility
Animal Models
Colon
Oxidative Stress
Myenteric Plexus
Housekeeping
Purines
NG-Nitroarginine Methyl Ester
Recycling
Carbachol
Atropine
Knockout Mice
Lipid Peroxidation
Acetylcholine
Free Radicals
Reactive Oxygen Species

All Science Journal Classification (ASJC) codes

  • Endocrine and Autonomic Systems
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease. / Mule', Flavia; Serio, Rosa Maria; Belluardo, Natale; Mudo', Giuseppa; Zizzo, Maria Grazia; Nuzzo, Domenico; Condorelli, Daniele F.; Caciagli, Francesco; Jinnah, Hyder A.; Di Iorio, Patrizia; Ciccarelli, Renata; Nuzzo, Domenico; Frinchi, Monica.

In: AUTONOMIC NEUROSCIENCE: BASIC & CLINICAL, 2018.

Risultato della ricerca: Article

Mule', Flavia ; Serio, Rosa Maria ; Belluardo, Natale ; Mudo', Giuseppa ; Zizzo, Maria Grazia ; Nuzzo, Domenico ; Condorelli, Daniele F. ; Caciagli, Francesco ; Jinnah, Hyder A. ; Di Iorio, Patrizia ; Ciccarelli, Renata ; Nuzzo, Domenico ; Frinchi, Monica. / Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease. In: AUTONOMIC NEUROSCIENCE: BASIC & CLINICAL. 2018.
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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.",
author = "Flavia Mule' and Serio, {Rosa Maria} and Natale Belluardo and Giuseppa Mudo' and Zizzo, {Maria Grazia} and Domenico Nuzzo and Condorelli, {Daniele F.} and Francesco Caciagli and Jinnah, {Hyder A.} and {Di Iorio}, Patrizia and Renata Ciccarelli and Domenico Nuzzo and Monica Frinchi",
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T1 - Altered gastrointestinal motility in an animal model of Lesch-Nyhan disease

AU - Mule', Flavia

AU - Serio, Rosa Maria

AU - Belluardo, Natale

AU - Mudo', Giuseppa

AU - Zizzo, Maria Grazia

AU - Nuzzo, Domenico

AU - Condorelli, Daniele F.

AU - Caciagli, Francesco

AU - Jinnah, Hyder A.

AU - Di Iorio, Patrizia

AU - Ciccarelli, Renata

AU - Nuzzo, Domenico

AU - Frinchi, Monica

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

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