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Several low\u2010molecular weight (poly)phenol metabolites (LMWPM) are found in the plasma after consumption of (poly)phenol\u2010rich 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>This study investigates\u00a0the neuroprotective potential of two blood\u2010brain barrier permeant LMWPM, catechol\u2010<jats:italic>O<\/jats:italic>\u2010sulfate (cat\u2010sulf), and pyrogallol\u2010<jats:italic>O<\/jats:italic>\u2010sulfate (pyr\u2010sulf),\u00a0in a human 3D cell model of PD. Neurospheroids were generated from LUHMES neuronal precursor cells and challenged by 1\u2010methyl\u20104\u2010phenylpyridinium (MPP<jats:sup>+<\/jats:sup>) to induce neuronal stress. LMWPM pretreatments were differently neuroprotective towards MPP<jats:sup>+<\/jats:sup> insult, presenting distinct effects on the neuronal transcriptome. Particularly, cat\u2010sulf pretreatment appeared to boost counter\u2010regulatory defense mechanisms (preconditioning). When MPP<jats:sup>+<\/jats:sup> is applied, both LMWPM positively modulated glutathione metabolism and heat\u2010shock response, as also favorably shifting the balance of pro\/anti\u2010apoptotic proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings point to the potential of LMWPM to trigger molecular mechanisms that help dopaminergic neurons to cope with a subsequent toxic insult. 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