3-Hydroxypyridin-4-one based derivatives as promising neuroprotective agents for Parkinson’s disease

• Autor(es): Silva , V. ; Benfeito, S. ; Lima , C. ; Chavarria, D. ; Gonçalves, T. ; Costa , I. ; Remião , F. ; Borges, F. ; Silva , R.
• Data: 2023
• Origem: Scientific Letters
• Assunto(s): Poster
• Tipo de Documento: Artigo científico
• Idioma: Inglês

Descrição

Background: Parkinson’s Disease (PD) is a multifactorial, complex and progressive neurodegenerative disease, characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta [1,2]. Several pathophysiological mechanisms are involved in PD, namely Lewy bodies formation, mitochondrial dysfunction, neuroinflammation, oxidative stress and iron accumulation within the brain [3]. Iron triggers ferroptosis, a form of cell death characterized by uncontrolled lipid peroxidation, glutathione (GSH) depletion and decreased glutathione peroxidase 4 (GPx4) activity [4]. The drugs currently available to treat PD predominantly aim to relieve symptoms [5]. Therefore, there is an urgent demand for an effective treatment capable to stopping or slowing the disease progression. Objective: The main goal of this study was to evaluate, in vitro, the cytotoxicity and the neuroprotective effects of a small library of 3-hydroxypyridin-4-one based derivatives. Methods: Differentiated SH-SY5Y cells (dopaminergic phenotype) were used as in vitro model. The compounds’ cytotoxicity was evaluated, 24h after exposure, by the neutral red uptake and resazurin reduction assays, to select the non-cytotoxic concentrations. To evaluate the potential neuroprotective effects of the compounds, cells were exposed for 24h to i) ferric nitrilotriacetate (FeNTA), a ferric (Fe3+) iron aggressor, ii) tert-butyl hydroperoxide (t-BHP), an organic peroxide capable of inducing oxidative stress-mediated cell death, or iii) (1S,3R)-RSL3 (RSL3), a ferroptosis inducer that acts by inhibiting GPX4. The exposures were performed in the absence or presence of the test compounds. Results: In general, the compounds showed a safe cytotoxic profile for concentrations up to 5 mM. Noteworthy, several derivatives showed significant, concentration-dependent protective effects against t-BHP, FeNTA and RSL3, highlighting their promising neuroprotective effects. Conclusions: In conclusion, the 3-hydroxypyridin-4-one based derivatives demonstrated a multitarget mode of action, highlighting their potential as promising neuroprotective agents for PD treatment.