Neuroprotection in a 3D Cell Model of Parkinson's Disease

Funding Information: This work was supported by European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program under grant agreement No. 804229; iNOVA4Health – UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through national funds. FCT/MCTES, through the project PTDC/BTM‐ORG/29580/2017. Authors would like to acknowledge FCT for financial support of R.C. (PD/BD/135492/2018) and J.G.‐P. (SFRH/BD/145522/2019). M.L. was supported by the Land‐BW (NAM‐ACCEPT) and funding by the European Union's Horizon 2020 research and innovation program under grant agreements No. 964537 (RISK‐HUNT3R), No. 964518 (ToxFree), and No. 825759 (ENDpoiNTs). Publisher Copyright: © 2022 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbHScope: Diets rich in (poly)phenols have been associated with positive effects on neurodegenerative disorders, such as Parkinson's disease (PD). Several low-molecular weight (poly)phenol metabolites (LMWPM) are found in the plasma after consumption of (poly)phenol-rich food. It is expected that LMWPM, upon reaching the brain, may have beneficial effects against both oxidative stress and neuroinflammation, and possibly attenuate cell death mechanisms relate to the loss of dopaminergic neurons in PD. Methods and Results: This study investigates the neuroprotective potential of two blood-brain barrier permeant LMWPM, catechol-O-sulfate (cat-sulf), and pyrogallol-O-sulfate (pyr-sulf), in a human 3D cell model of PD. Neurospheroids were generated from LUHMES neuronal precursor cells and challenged by 1-methyl-4-phenylpyridinium (MPP+) to induce neuronal stress. LMWPM pretreatments were differently neuroprotective towards MPP+ insult, presenting distinct effects on the neuronal transcriptome. Particularly, cat-sulf pretreatment appeared to boost counter-regulatory defense mechanisms (preconditioning). When MPP+ is applied, both LMWPM positively modulated glutathione metabolism and heat-shock response, as also favorably shifting the balance of pro/anti-apoptotic proteins. Conclusions: Our findings point to the potential of LMWPM to trigger molecular mechanisms that help dopaminergic neurons to cope with a subsequent toxic insult. They are promising molecules to be further explored in the context of preventing and attenuating parkinsonian neurodegeneration.publishersversionepub_ahead_of_prin