PROJECT TYPE: University Supported Scientific Research Projects (BAP)

PROJECT NO: 2022-04-02-MAP01

SUMMARY:

Neurodegenerative diseases are associated with lesions occurring in the central nervous system and pathology occurring in the enteric nervous system. Especially in neurodegenerative diseases such as Parkinson's disease (PD), in which non-motor findings increase in severity and accompany the disease, symptoms affecting the gastrointestinal system are among the earliest findings. Studies show that pathological findings of PH are also detected in the enteric nervous system. Enteroglial cells (EGCs) within the enteric nervous system represent the equivalent of astrocytes in the brain and are an important component of the inflammatory response. These cells become active in the presence of inflammation, increase the levels of S100B, a chemotactic factor, and cause the secretion of proinflammatory cytokines and cell damage by activating the receptor for advanced glycation end products (RAGE). Neurotoxin models are frequently used to mimic PD-like pathology in vivo or in vitro experimentally. Rotenone is a pesticide that can successfully mimic motor and non-motor manifestations of PH. Although there are studies examining the effects of rotenone on neurons and glial cells in the central nervous system, no study illuminates its direct effect on enteroglial cells. Antidepressants are frequently studied in neuroinflammation studies because they were found beneficial in inflammatory diseases. Vortioxetine, a multimodal serotonergic antidepressant, is a valuable molecule thought to have antioxidant and anti-inflammatory effects. This study aims to elucidate the in vitro effects of vortioxetine, which has been previously shown to alleviate motor and non-motor findings in an in vivo PD model, on the pathophysiological changes induced by rotenone in enteroglial cells. For this purpose, inflammation will be triggered by rotenone exposure in the rat-derived enteroglial cell line (ATCC®CRL-2690™), and the changes in the levels of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and other molecules involved in the inflammatory process (S100B, RAGE and phospho-NFKB-p65) with vortioxetine administration will be analyzed. To elucidate the role of the S100B/RAGE signaling pathway in the effects of rotenone or vortioxetine, cells will be treated with a RAGE antagonist and parameters reassessed. A new in vitro model will be defined to test approaches that can prevent enteric neurodegeneration with this study. It will also pave the way for exploring new pathways for the treatment of neurodegenerative diseases.

01/03/2022 →