Circulating (Poly)phenol Metabolites: Neuroprotection in a 3D Cell Model of Parkinson's Disease

Abstract

Scope: 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.

Circulating (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood-brain barrier transport

“…Knowing the three (poly)phenol metabolites transport kinetics across the endothelial cells of the BBB, and bearing in mind that at least one of them, Pyr-sulf, presented pleiotropic potential against oxidative stress, glutamate excitotoxicity, neuroinflammation and dopaminergic cell death[12, 22], we wondered what their contribution could be to improve barrier tightness. To this end, HBMEC were incubated with each of the metabolites at 5μM for 2h, and the expression of both β-catenin and ZO-1 were assessed by fluorescence microscopy ( Figure 2 ), key proteins for AJs and TJs, respectively.…”

“…Moreover, in silico analysis suggested that none of these would be able to cross the BBB endothelium solely by passive permeation, thus active transport might be involved [12]. Remarkably, pre-treatment with these BBB permeable phenolic sulfates, in circulating concentrations, shown to improve cellular responses to excitotoxicity and oxidative and inflammatory injuries, particularly via modulation of NF-κB pathway [12] and two of them are strong attenuators of neurodegeneration against a dopaminergic insult in a three-dimensional neuronal model [22]. Such observations support our hypothesis that LMW (poly)phenol metabolites can be the true responsible for the reported brain health benefits arising from (poly)phenol reach diets.…”

Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

“…In addition, polyphenols at dietary concentrations have been connected with the prevention and attenuation of PD through alternative mechanisms, including oxidative stress (i.e., a reduction of reactive oxygen species) and neuroinflammation reduction 211,212 .…”

Do (Poly)phenols Matter for Nutrition Research? News from the Front

“…An optimized highthroughput imaging approach was used and some phenyl-𝛾valerolactones and phenolic acids were able to inhibit spheroid aggregation. Spheroids were also used by Carecho et al [8] to demonstrate the neuroprotective effects of two phenolic metabolites that are able to cross the blood-brain barrier on a human 3D cell model of Parkinson's disease. This further supports the role of (poly)phenol metabolites in brain (patho)physiology.…”

“…Spheroids were also used by Carecho et al. [ 8 ] to demonstrate the neuroprotective effects of two phenolic metabolites that are able to cross the blood‐brain barrier on a human 3D cell model of Parkinson's disease. This further supports the role of (poly)phenol metabolites in brain (patho)physiology.…”