Sa1694 Colonic Inflammation in Experimental Parkinson's Disease: Evidence of Altered Colonic Tachykininergic Neurotransmissio

Colonic Inflammation in Experimental Parkinson's Disease: Evidence of Altered Colonic Tachykininergic Neurotransmissio Matteo Fornai, Carolina Pellegrini, Luca Antonioli, Chiara Ippolito, Cristina Segnani, Giovanna Levandis, Silvia Cerri, Rocchina Colucci, Nunzia Bernardini, Fabio Blandini, Corrado Blandizzi Introduction. Parkinson's disease (PD) is characterized by the occurrence of digestive motor dysfunctions. In patients with PD there are also signs of enteric inflammation, that could take part to the altered patterns of gut motility. This study examined the occurrence of colonic inflammation and the patterns of colonic excitatory motility driven by tachykininergic pathways in a rat model of PD. Methods. PD was induced in rats by intra-nigral injection of 6-hydroxydopamine (6-OHDA). Animals were euthanized 4 or 8 weeks after 6-OHDA injection. Colonic longitudinal muscle preparations were set up in organ baths with Krebs solution, and connected to isometric transducers to record contractions (expressed as g/g of tissue) elicited by electrical stimulation (ES, 10 Hz, 0.5 ms, 30 mA). The experiments were carried out in the presence of guanethidine (10 µM), Nω -nitro-L-arginine methylester (L-NAME, 100 µM) and atropine (1 µM) to record contractile responses driven primarily by tachykinins. Contractions elicited by exogenous substance P (SP, 10 µM), in the presence of tetrodotoxin (1 µM), were also assessed. The expression and localization of SP, neurokinin- 1 (NK1 ) receptors and glial fibrillary acidic protein (GFAP, marker of glial cell expression), as well as the density of mast cells and eosinophil in the colonic wall were assessed by immunohistochemistry and histochemistry. Colonic levels of malondialdehyde (MDA), tumor necrosis factor (TNF) and interleukin-1β (IL-1β) were evaluated by ELISA. Results. Electrically evoked tachykininergic contractions in longitudinal muscle preparations were enhanced in rats euthanized 4 and 8 weeks after 6-OHDA injection, as compared with controls. Likewise, contractile responses elicited by exogenous SP in colonic preparations from PD rats were increased, both at week 4 and 8. The expression of SP and GFAP in the myenteric plexus as well as NK1 receptors in the longitudinal muscle layer were enhanced in rats with PD, both at week 4 and 8. The density of eosinophils and mast cells in the mucosa and submucosa of colonic tissues from rats with PD was increased. The levels of MDA, TNF and IL-1β were also elevated in colonic samples from PD rats, both at week 4 and 8, as compared to colonic tissues from controls. The overall data are summarized in the table. Conclusion. Central nigrostriatal dopaminergic denervation, a hallmark of PD, is associated with an enhancement of colonic excitatory tachykininergic neurotransmission, that occurs along with oxidative stress, tissue inflammation and glial activation. It is suggested that central dopaminergic denervation triggers a condition of gut inflammation, which could contribute to enteric dysmotility