PROJECT TYPE: 1002-Fast Support

PROJECT NUMBER: 121R103

SUMMARY:

Parkinson's disease (PD), defined as a movement disorder, is a neurodegenerative disease in which many non-motor symptoms such as cognitive dysfunction, sleep disorders, psychiatric symptoms, and gastrointestinal (GI) dysfunction are commonly present. Studies show that PD pathology is also detected in the enteric nervous system (ENS) and that PD is even based on the gut-brain axis. Enteroglial cells (EGCs) within the ENS 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 and increase the secretion of chemotactic factors such as S100B. By acting as a damage-associated molecular pattern (DAMP), the S100B protein stimulates Toll-like receptors (TLR) and activates proinflammatory signaling pathways. Rotenone, a lipophilic pesticide, is frequently used in vivo and in vitro models to mimic PD-like pathology experimentally. Studies have shown that systemic rotenone administration induces neuropathological changes not only in the central nervous system but also in ENS in animals, causing GI dysfunction as well as motor and non-motor symptoms. This planned study aims to elucidate the effects of vortioxetine, a multimodal serotonergic antidepressant, which was previously shown to alleviate motor and non-motor findings in an in vivo PD model, on enteric pathology using in vivo and in vitro methods. For this purpose, histopathological and immunohistochemical analyses (Tyrosine hydroxylase, α-synuclein, serine-129 phosphorylated α-synuclein, TLR-2 and S100B) will be performed in duodenal tissue of rats with PD-like pathology mimicked by rotenone administration. Then, rotenone-mediated inflammation will be triggered in the rat-derived enteroglial cell line (ATCC®CRL-2690™). The changes in the levels of proinflammatory cytokines (TNFα, IL-1β and IL-6) and other molecules involved in the inflammatory process (S100B, TLR-2 and phospho-NFKB-p65) levels with vortioxetine treatment will be determined. In order to elucidate the role of the TLR-2/S100B signaling pathway in the effects of rotenone or vortioxetine, cells will be treated with TLR-2 antagonist, and parameters will be reassessed. Thus, the effects of vortioxetine on enteric pathology in PD will be examined for the first time in an experimental PD model, and a new pathway for the treatment of non-motor symptoms in PD will be determined as a target, thanks to the in vitro model designed by administering rotenone to EGCs.

01/03/2022 → 01/03/2023