A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

Abstract

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.

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…As mentioned, α-Syn is an unfolded protein that accumulates in Lewy bodies, a hallmark of PD [ 111 ]. Aminochrome, on the other hand, is an endogenous DA neurotoxin [ 11 ]. Compared to microglia, astrocytes are not well equipped with receptors that can recognize pathogens.…”

“…On the other hand, recessive DNAJC6 mutations can present as atypical Parkinsonism [ 7 ]. Additionally, the potential contribution of environmental toxins, such as herbicides (e.g., paraquat), insecticides (e.g., rotenone), an excess accumulation of iron or manganese [ 3 , 8 , 9 , 10 ], as well as exposure to endogenous toxins such as salsolinol or aminochrome, to PD pathology was verified [ 3 , 11 , 12 ].…”

Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury

“…Ferroptosis is a novel mode of iron-dependent cell death induced by lipid peroxidation, which is distinguished from apoptosis, necrosis, pyroptosis and autophagy, and is mainly characterised by iron accumulation and lipid peroxidation. 5 Numerous studies have found that ferroptosis is involved in a variety of diseases including neurodegeneration, 6 stroke, 7 cerebral haemorrhage, 8 and AKI 9 and that targeting the activation or inhibition of the pathways corresponding to ferroptosis can intervene in the onset and progression of disease. It was found that iron overload induced ferroptosis in renal tubular epithelial cells and was involved in the development of AKI.…”

Oxidative Stress-Induced Neurodegeneration and Antioxidative Strategies: Current Stage and Future Perspectives

“…These articles aim to review the recent findings in the ND field and highlight the gaps in knowledge and future research directions. The reviews cover important directions such as (i) the identification of new potential biomarkers for age-related ND disease progression that can be modulated for therapeutic purposes [ 10 ]; (ii) the development of a new preclinical model for PD to test new potential drugs, with an increased potential to limit disease progression or cure it [ 11 ]; (iii) the role of nutraceuticals and physical exercise in controlling oxidative balance and improving functional outcomes in NDs [ 12 , 13 ]; (iv) mitochondrial function and oxidative stress in relation to successful cellular therapy for stroke [ 14 ].…”

“…Juan Segura-Aguilar and his colleagues studied a KEAP1/NRF2 transcriptional activation preclinical model for PD, because no current treatments for PD are guaranteed to work, and no one has studied the effect of antioxidants on idiopathic PD [ 11 ]. This model will be useful for the development of new potential antioxidant therapies [ 11 ].…”