id_949. NEUROPROTECTIVE ACTION OF TRAMIPROSATE IN A ROTENONE-BASED CELLULAR MODEL OF PARKINSON’S DISEASE
Ajay Modi1,2, Sheetal Maria1,2, Jiří Damborský3,4,5, Martin Marek3,4,5, Amit Khairnar1,2,6
1 Center for Translational Medicine, ICRC, St. Anne’s University Hospital Brno, Czech Republic
2 Faculty of Medicine, Masaryk University, Brno, Czech Republic
3 Loschmidt Laboratories, Faculty of Science, Masaryk University, Brno, Czech Republic
4 RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
5 ICRC, St. Anne’s University Hospital Brno, Czech Republic
6 Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
INTRODUCTION: Parkinson’s disease (PD) is a chronic neurodegenerative disorder marked by the progressive degeneration of dopaminergic neurons and pathological aggregation of α-synuclein (αSyn). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are key contributors to disease progression. Rotenone, a mitochondrial complex I inhibitor, is commonly used to reproduce PD-like cellular pathology. Tramiprosate, an amyloid aggregation inhibitor developed for Alzheimer’s disease, has recently shown potential neuroprotective effects; however, its role in PD has not yet been fully explored.
AIM(S): To investigate whether tramiprosate protects human dopaminergic SH-SY5Y cells from rotenone-induced neurotoxicity and to elucidate the underlying molecular mechanisms.
METHOD(S): SH-SY5Y cells were pre-treated with tramiprosate (1–400 µM) before rotenone exposure, and viability was evaluated using the Alamar Blue assay. Mechanistic studies were conducted using 20 µM tramiprosate pre-treatment for 24 h, followed by gene expression analysis (RT-PCR) and protein localization studies (immunocytochemistry).
RESULTS: Tramiprosate significantly enhanced cell survival across all tested concentrations. At 20 µM, tramiprosate restored tyrosine hydroxylase (TH) expression and reduced phosphorylated αSyn. It selectively altered αSyn isoform expression by increasing αSyn-140 and APOE levels while decreasing αSyn-126 and αSyn-98, with no change in αSyn-112. Tramiprosate also reduced oxidative stress–associated p47phox transcripts, without affecting NOX2 or NOX4. Inflammatory markers TNF-α and NFκB were downregulated, whereas the anti-inflammatory cytokine IL-10 was elevated. Furthermore, tramiprosate decreased both the number and size of lipid droplets despite an overall increase in total αSyn expression.
CONCLUSIONS: In conclusion, tramiprosate exerts strong neuroprotective effects in a rotenone-based cellular model of PD by modulating αSyn processing, oxidative stress, inflammation, and lipid metabolism.
FINANCIAL SUPPORT: We acknowledge the financial supports provided by the project “VGF peptides as protective agents against neurodegeneration” (MUNI/11/EDUC HE/2025); the European Union–funded project “Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe” (Grant No. 101087124); and “Od preklinického ke klinickému výzkumu 2” (MUNI/A/1795/2025).