Investigations of the effect of
antioxidants on
idiopathic Parkinson's disease have been unsuccessful because the preclinical models used to propose these clinical studies do not accurately represent the neurodegenerative process of the disease. Treatment with certain exogenous
neurotoxins induces massive and extremely rapid degeneration; for example,
MPTP causes severe
Parkinsonism in just three days, while the degenerative process of idiopathic Parkinson´s disease proceeds over many years. The endogenous
neurotoxin aminochrome seems to be a good alternative target since it is formed in the nigrostriatal system neurons where the degenerative process occurs.
Aminochrome induces all the mechanisms reported to be involved in the degenerative processes of
idiopathic Parkinson's disease. The presence of
neuromelanin-containing dopaminergic neurons in the postmortem brain of healthy elderly people suggests that
neuromelanin synthesis is a normal and harmless process despite the fact that it requires oxidation of
dopamine to three ortho-
quinones that are potentially toxic, especially
aminochrome. The apparent contradiction that
neuromelanin synthesis is harmless, despite its formation via neurotoxic ortho-
quinones, can be explained by the protective roles of
DT-diaphorase and
glutathione transferase GSTM2-2 as well as the neuroprotective role of astrocytes secreting exosomes loaded with GSTM2-2. Increasing the expression of
DT-diaphorase and GSTM2-2 may be a therapeutic goal to prevent the degeneration of new
neuromelanin-containing dopaminergic neurons. Several
phytochemicals that induce
DT-diaphorase have been discovered and, therefore, an interesting question is whether these
phytochemical KEAP1/NRF2 activators can inhibit or decrease
aminochrome-induced neurotoxicity.