Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration.
Parkinson'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.



Animals 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.



In 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.



The 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.
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Carolina
C
Pellegrini
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy. mfornai74@gmail.com.
Matteo
M
Fornai
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy.
Rocchina
R
Colucci
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Erika
E
Tirotta
Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, 27100, Pavia, Italy.
Fabio
F
Blandini
Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, 27100, Pavia, Italy.
Giovanna
G
Levandis
Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, "C. Mondino" National Neurological Institute, 27100, Pavia, Italy.
Silvia
S
Cerri
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Cristina
C
Segnani
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Chiara
C
Ippolito
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Nunzia
N
Bernardini
Department of Medical Chemistry, Medical and Health Science Center, University of Debrecen, Debrecen, 4032, Hungary.
Karolina
K
Cseri
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Corrado
C
Blandizzi
Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, 07103, NJ, USA.
György
G
Haskó
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.|Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, 07103, NJ, USA.
Luca
L
Antonioli
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D017615:Enteric Nervous System / Q000187:drug effects / Q000502:physiology; D004804:Eosinophils / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000209:etiology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001583:Benzoxazoles; C092990:GR 159897; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C480767:SB219994; D013565:Sympatholytics; D013373:Substance P; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
6-hydroxydopamine; Colonic motility; Inflammation; Parkinson’s disease; Substance P; Tachykininergic neurotransmission