Abstract
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. This study investigatesthe 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. 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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the first motor debilitating degenerative disease.[1,2] PD is a chronic pathology that affects the brain due to the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of protein aggregates containing αsynuclein.[3]
PD symptoms result from a decrease in dopamine levels which might be caused by a disturbance in dopamine exchange system.[3]
It has been shown that oxidative stress is central to the pathology of this disease.[5]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the first motor debilitating degenerative disease.[1,2] PD is a chronic pathology that affects the brain due to the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of protein aggregates containing αsynuclein.[3]. In particular colonic-derived phase II metabolites of dietary (poly)phenols were identified in biological samples of human volunteers which took a berries mixture,[15,16] cranberries,[17] mango,[18] or black tea.[19] These sulfates, when tested in circulating concentrations (5 μM), were shown to be significantly transported across an in vitro model of the blood-brain barrier (BBB),[20] holding great promise as possible braintargeted compounds These metabolites, in particular catechol-O-sulfate (cat-sulf) and pyrogallol-O-sulfate (pyr-sulf), presented strong neuroprotective and anti-neuroinflammatory activity against common neurodegeneration hallmarks in vitro.[20] their role in the context of PD is still unexplored. Both were able to modulate several genes mainly involved in stress response, and have shown ability to interfere with glutathione metabolism, comprising promising new molecules to be further explored in the scope of PD
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