Effects of L-DOPA/Benserazide Co-Treatment on Colonic Dysmotility and Enteric Inflammation Following Dopaminergic Nigrostriatal Neurodegeneration

Introduction. Gastrointestinal disturbances in Parkinson's disease (PD) are prominent non- motor features of the disease, mainly represented by digestive motor abnormalities associated with bowel inflammation (Pellegrini C et al. J Neuroinflammation 2016 13:146). The mainstay treatment of PD is represented by levodopa (L-DOPA) plus DOPA-decarboxylase inhibitors. However, the possible influence of these drugs on colonic inflammation and dysmotility in PD are unknown. This study examined the effects of L-DOPA plus benserazide (L-DOPA/ BE) on alterations of colonic motility and inflammatory markers in rats with 6-hydroxydopa- mine (6-OHDA)-induced central nigrostriatal denervation. Methods. PD was induced in male rats by intranigral injection of 6-OHDA or vehicle (sham-6-OHDA). 6-OHDA or sham- 6-OHDA animals were administered orally with L-DOPA/BE (6/15 mg/Kg/day) or their vehicle for 28 days, starting 28 days after intranigral treatment. At the end of treatments, in vivo colonic transit was evaluated by radiologic assay. In particular, 56 days after 6-OHDA or saline injection, fasted untreated and L-DOPA/BE-treated rats received a suspension of BaSO (2.5 ml, 1.5 g/ml) intragastrically, and radiographic exposures were taken 12 hours later. The proportion of labeled colorectum, intensity of labeling, organ profile and intralumi- nal labeling homogeneity were evaluated and scored (from 0 to 12). Glial fibrillary acidic protein (GFAP) expression in myenteric ganglia, as well as eosinophil and mast cell density in the colonic mucosa-submucosa were assessed by immunohistochemistry. Tumor necrosis factor (TNF), interleukin (IL)-1β (ELISA assay) and malondialdehyde (MDA, colorimetric assay) tissue levels were examined. Results. In sham-6-OHDA animals, treatment with L- DOPA/BE did not modify all the evaluated parameters, as compared with drug vehicle treatment. When compared with sham-6-OHDA rats, 6-OHDA animals displayed the following changes: 1) decreased in vivo colonic transit rate; 2) increase in TNF, IL-1β and MDA levels; 3) increase in GFAP levels; 4) increase in eosinophil and mast cell density. In 6-OHDA animals, treatment with L-DOPA/BE was associated with a significant improvement of in vivo colonic transit. In addition, treatment of 6-OHDA rats with L-DOPA/BE normalized the pro-inflammatory cytokines and GFAP levels, as well as the eosinophil and mast cell density, without affecting the increased level of oxidative stress. The results are summarized in the table. Conclusion. The present findings confirm and expand our previous observations on the occurrence of colonic motor dysfunctions and inflammation arising from nigrostriatal dopaminergic denervation. Most importantly, the L-DOPA/BE treatment, commonly used in PD to counteract the central dopaminergic deficiency, also appears to resolve the related condition of bowel dysmotility and inflammation.