Abstract
BackgroundParkinson’s disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions. The mechanisms underlying such disorders are still largely unknown, although the occurrence of a bowel inflammatory condition has been hypothesized. This study examined the impact of central dopaminergic degeneration, induced by intranigral injection of 6-hydroxydopamine (6-OHDA), on distal colonic excitatory tachykininergic motility in rats.MethodsAnimals were euthanized 4 and 8 weeks after 6-OHDA injection. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. SP, tachykininergic NK1 receptor, and glial fibrillary acidic protein (GFAP) expression, as well as the density of eosinophils and mast cells in the colonic wall, were examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay), TNF, and IL-1β (ELISA assay) levels were also examined. The polarization of peritoneal macrophages was evaluated by real-time PCR.ResultsIn colonic preparations, electrically and SP-evoked tachykininergic contractions were increased in 6-OHDA rats. Immunohistochemistry displayed an increase in SP and GFAP levels in the myenteric plexus, as well as NK1 receptor expression in the colonic muscle layer of 6-OHDA rats. MDA, TNF, and IL-1β levels were increased also in colonic tissues from 6-OHDA rats. In 6-OHDA rats, the number of eosinophils and mast cells was increased as compared with control animals, and peritoneal macrophages polarized towards a pro-inflammatory phenotype.ConclusionsThe results indicate that the induction of central nigrostriatal dopaminergic degeneration is followed by bowel inflammation associated with increased oxidative stress, increase in pro-inflammatory cytokine levels, activation of enteric glia and inflammatory cells, and enhancement of colonic excitatory tachykininergic motility.
Highlights
Parkinson’s disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions
Animals injected with 6-OHDA vehicle and sacrificed after 8 weeks were selected as controls, since preliminary experiments, performed with the specific aim of comparing animals injected with 6OHDA vehicle and sacrificed at 4 and 8 weeks, did not show any significant difference in electrically evoked colonic tachykininergic contractions
The significance of differences was evaluated by Student t test for unpaired data or one-way analysis of variance (ANOVA) followed by post hoc analysis with Student-Newman-Keuls or Bonferroni tests
Summary
Parkinson’s disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions. Alterations of enteric neurotransmitters (dopamine, nitric oxide, vasoactive intestinal peptide, acetylcholine), all involved in the regulation of intestinal motility, have been documented in the 6-OHDA model, suggesting that central dopaminergic neurodegeneration is associated with remodeling of enteric neurotransmission [9,10,11,12]. In this context, very scarce attention has been paid to the possible involvement of enteric tachykininergic pathway in the pathophysiology of gut motor dysfunctions associated with PD. This is quite surprising, in view of the evidence that intrinsic enteric tachykininergic nerves play a pivotal role in the physiological regulation of GI motility and that such system undergoes significant rearrangements under pathological conditions, including bowel motor dysfunctions associated with inflammatory disorders [13, 14]
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