3-Hydroxypyridin-4-one based derivatives as promising neuroprotective agents for Parkinson’s disease
DOI:
https://doi.org/10.48797/sl.2023.90Keywords:
PosterAbstract
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.
References
1. Simon, D.K.; Tanner, C.M.; Brundin, P. Parkinson’s disease epidemiology, pathology, genetics, and patho-physiology. Clin Geriatr Med 2020, 36, 1-12.
2. Raza C.; Anjum R.; Shakeel, N.U.A. Parkinson's disease: Mechanisms, translational models and management strategies. Life Sciences 2019, 226, 77-90.
3. Kouli, A.; Torsney, K.M.; Kuan, W.L. Parkinson's disease: etiology, neuropathology, and pathogenesis. In Parkinson's Disease: Pathogenesis and Clinical Aspects, 2nd ed.; Stoker, T.B., Greenland, J.C., Eds.; Publisher: Brisbane, Australia, 2018; Section 1.
4. Moreau, C.; Duce, A.J.; Rascol, O.; Devedjian, J.C.; Berg, D.; Dexter, D.; Cabantchik, Z.l.; Bush, A.I.; Devos, D. Iron as a therapeutic target for Parkinson's disease. Mov Disord 2018, 33, 568-574.
5. Dong, J.; Yanhua, C.; Song, L.; Weidong, L. Current pharmaceutical treatments and alternative therapies of Parkinson's disease. Curr Neuropharmacol 2016, 14, 339-355.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 V. Silva , S. Benfeito, C. Lima , D. Chavarria, T. Gonçalves, I. Costa , F. Remião , F. Borges, R. Silva
This work is licensed under a Creative Commons Attribution 4.0 International License.
In Scientific Letters, articles are published under a CC-BY license (Creative Commons Attribution 4.0 International License), the most open license available. The users can share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as they give appropriate credit, provide a link to the license, and indicate if changes were made (read the full text of the license terms and conditions of use).
The author is the owner of the copyright.
