The ability of dietary polyphenols to protect against endogenously-formed neurotoxins

Parkinson disease is characterized by a progressive and selective loss of dopaminergic neurons in the substantia nigra. Although the mechanisms by which these neurons degenerate is unclear, accumulating evidence suggests that endogenously formed 5-S-cysteinyl-dopamine (CysDA) conjugates, formed during the oxidation of dopamine in the present of cysteine (or other cellular thiols) may contribute to nigral death1. Recent investigations have shown that CysDA possesses strong neurotoxicity and may initiate a sustained increase in intracellular reactive oxygen species (ROS) in neurons leading to DNA oxidation, caspase-3 activation and delayed neuronal death2. In addition, CysDA may undergo further oxidation to yield new species, such as dihydrobenzothiazine, which have been reported to be potent mitochondrial respiratory complex I inhibitors3. Recently there has been intense interest in the effects of dietary antioxidants and polyphenolic compounds, present in fruits and vegetables, to protect against neuronal damage and cognitive decline4. Whilst flavonoids may exert their biological effects via their antioxidant capacity, there is accumulating evidence suggesting that they might exert neuromodulatory activities through the modulation of cellular signalling pathways, in particular the mitogen activated protein kinase (MAPK) pathway5. This study focused on the ability of dietary derived polyphenols to protect against neurotoxicity exerted by endogenously formed CysDA and derived species. In vitro experiments demonstrated that CysDA may be formed during the oxidation of dopamine by tyrosinase or peroxynitrite. However, in presence of polyphenols (resveratrol, hesperetin, caffeic acid and (+)-catechin) a small but significant decrease in CysDA formation was observed. Moreover, these reactions led to the formation of various polyphenol-cysteinyl adducts, which may represent novel metabolic forms present in vivo. Caffeic acid, gallic acid and tyrosol also exerted strong protection against peroxynitrite-induced injury to primary cortical neurons (Figure 1), whilst hesperetin and pelargonidin were observed to protect against CysDA neurotoxicity. The mechanism by which polyphenols inhibited neuronal death was found to be linked to their ability to induce the activation of both Akt/PKB signalling and the ERK1/2 pathways. The protective effects of polyphenols against neurotoxins-induced toxicity will help shed light on their mechanism of neuroprotection.