MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut

Gianfranco Natale, Olga Kastsiushenka, Federica Fulceri, Stefano Ruggieri, Antonio Paparelli, Francesco Fornai

Research output: Contribution to journalArticlepeer-review

Abstract

Gastrointestinal (GI) dysfunction occurs frequently in early Parkinson's disease (PD) and it is supposed to anticipate motor symptoms. About 80% of PD patients suffer from constipation before the onset of movement disorders. Despite such a high prevalence of gut impairment in PD, the molecular mechanisms remain poorly investigated. This is also due to the scarcity of experimental studies. In the present work, we tried to reproduce digestive abnormalities observed in PD patients by administering the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) to C57BL mice. We show that in these mice, MPTP (20 mg/kg × 3) while producing the classic striatal dopamine (DA) denervation, persistently delays colonic motility, produces constipation, and reduces the number of enteric TH-positive neurons. The loss of TH-positive cells in the gut is selectively due to the disappearance of DA neurons within both myenteric and mostly submucosal plexus in the intestine, while no change is detected in the esophagus and stomach. In contrast, norepinephrine (NE) neurons are not affected. These data were confirmed by immunohistochemistry and by HPLC showing the significant loss of DA levels while NE and 5-HT content was not affected. Dopamine cell loss was associated with increased α-synuclein levels. These functional, biochemical, and morphological findings extend the PD-mimicking effects of MPTP to GI dysfunctions and provide a useful experimental model to understand gut dysfunction in PD and to find effective treatments for digestive symptoms.

Original languageEnglish
Pages (from-to)195-206
Number of pages12
JournalBrain Research
Volume1355
DOIs
Publication statusPublished - Oct 8 2010

Keywords

  • α-syn
  • 5-HT
  • 6-hydroxydopamine
  • 6-OHDA
  • alpha-synuclein
  • DA
  • DAT
  • dopamine
  • dopamine transporter
  • ENS
  • enteric nervous system
  • gastrointestinal
  • GI
  • H&E
  • haematoxylin and eosin
  • LC
  • locus coeruleus
  • MP
  • myenteric plexus
  • NE
  • NET
  • noradrenaline transporter
  • norepinephrine
  • Parkinson's disease
  • PD
  • SDS-PAGE
  • serotonin
  • sodium dodecyl sulphate-polyacrylamide gel electrophoresis
  • TH
  • tyrosine hydroxylase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

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