A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies
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 m...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/12/3/673 |
| _version_ | 1797613791407505408 |
|---|---|
| author | Juan Segura-Aguilar Bengt Mannervik |
| author_facet | Juan Segura-Aguilar Bengt Mannervik |
| author_sort | Juan Segura-Aguilar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T07:00:39Z |
| format | Article |
| id | doaj.art-8245bb6d8123478fab2fbc5999a85e1a |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T07:00:39Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-8245bb6d8123478fab2fbc5999a85e1a2023-11-17T09:18:10ZengMDPI AGAntioxidants2076-39212023-03-0112367310.3390/antiox12030673A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant TherapiesJuan Segura-Aguilar0Bengt Mannervik1Molecular & Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia, Santiago 8380000, ChileDepartment of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, SE-10691 Stockholm, SwedenInvestigations 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.https://www.mdpi.com/2076-3921/12/3/673dopamineParkinson’s diseaseneuromelaninantioxidantsaminochromeglutathione transferase M2-2 |
| spellingShingle | Juan Segura-Aguilar Bengt Mannervik A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies Antioxidants dopamine Parkinson’s disease neuromelanin antioxidants aminochrome glutathione transferase M2-2 |
| title | A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies |
| title_full | A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies |
| title_fullStr | A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies |
| title_full_unstemmed | A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies |
| title_short | A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies |
| title_sort | preclinical model for parkinson s disease based on transcriptional gene activation via keap1 nrf2 to develop new antioxidant therapies |
| topic | dopamine Parkinson’s disease neuromelanin antioxidants aminochrome glutathione transferase M2-2 |
| url | https://www.mdpi.com/2076-3921/12/3/673 |
| work_keys_str_mv | AT juanseguraaguilar apreclinicalmodelforparkinsonsdiseasebasedontranscriptionalgeneactivationviakeap1nrf2todevelopnewantioxidanttherapies AT bengtmannervik apreclinicalmodelforparkinsonsdiseasebasedontranscriptionalgeneactivationviakeap1nrf2todevelopnewantioxidanttherapies AT juanseguraaguilar preclinicalmodelforparkinsonsdiseasebasedontranscriptionalgeneactivationviakeap1nrf2todevelopnewantioxidanttherapies AT bengtmannervik preclinicalmodelforparkinsonsdiseasebasedontranscriptionalgeneactivationviakeap1nrf2todevelopnewantioxidanttherapies |