Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment
Abstract
:1. Introduction
2. Motoneurons Vulnerability to Oxidative Stress
3. Antioxidant Therapy in ALS
4. Nrf2 Involvement in ALS
5. Role of Glial Cells in ALS
6. Nrf2-Targeted Pharmacological Approach
7. Electrophilic Inhibitors of Keap1
8. Protein–Protein Interaction (PPI) Inhibitors of the Keap1-Nrf2 Complex
9. Other Ways for Nrf2 Activation
10. Issues in Drug Discovery Related to ALS
11. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Markers of Oxidative Stress | Experimental Model | Ref. |
---|---|---|
- MDA accumulation (lipid peroxidation) | SOD1G93A mouse model | [17] |
- Increase levels of MDA (lipid peroxidation) - Increased levels of 8-OHdG (oxidative DNA damage) - Increased GSSG/GSH ratio (oxidative stress). | Blood samples of SALS patients | [18] |
- Increased levels of 4-HNE (lipid peroxidation) | Post-mortem specimens of lumbar spinal cord and/or occipital cortex | [19] |
- Decreased GSH levels (oxidative stress) | Motor cortex of ALS patients | [20] |
- Increased levels of urinary 8-OhdG and IsoP (lipid peroxidation) | Urine of SALS patients | [21] |
- Increased HNE level (lipid peroxidation) | CSF of SALS patients | [22] |
- Increased HNE level (lipid peroxidation) | Serum and CSF of SALS patients | [23] |
- Increased protein carbonyl levels | Serum of SALS patients | [24] |
- Increased levels of adducts of HNEH and CRAL (lipid peroxidation) - Increased levels of CML and pentosidine (protein glycoxidation) | Postmorten spinal cords of SALS patients | [25] |
- Increase 8-OHG levels (DNA oxidation) | Postmortem brain and spinal cord tissues of ALS patients and SOD1G93A mouse model | [26] |
Mechanism of Nrf2 Activation | Compound | Model and trial | Outcome | Ref. |
---|---|---|---|---|
Electrophilic inhibition of Keap1-mediated Nrf2 degradation | Curcumin derivatives | SOD1H46R mouse model | Improved motor function | [110] |
Clinical trial NCT04499963 (ongoing) | ||||
Clinical trial as add-on therapy to riluzole (completed) | Increased probability of survival without changes in motor function. | [43] | ||
Resveratrol | SOD1G93A mouse model | Conflicting preclinical results | [111] | |
Combined treatment of resveratrol and curcumin | Clinical trial NCT04654689 (ongoing) | |||
CC100 | Clinical trial NCT03049046 (completed) | Short-term treatment is safe and tolerable. | [101] | |
DMF | Clinical trial as add-on to riluzole therapy ACTRN12618000534280 (completed phase II) | No improvement of survival and respiratory function | [81,98] | |
p62-mediated Keap1 degradation | Trehalose | SOD1G86R mouse model | Increased survival and attenuated disease progress in mouse models. | [112] |
SOD1G93A mouse model | Postponed disease onset, slowed down disease progress, no changes in survival. | [113] | ||
Clinical trial NCT05136885 (ongoing) | ||||
Rapamycin | p62 knockdown zebrafish model | Imrpoved motor function | [114] | |
TDP-43 Drosophila model | Partially improved survival and motor function | [115] | ||
Clinical trial NCT03359538 (ongoing) | ||||
Inhibition of GSK3β-promoted Nrf2 degradation by phosphorylation | Tideglusib | TDP-43 transgenic mice | Reduced TDP-43 phosphorylation in the spinal cord of TDP-43 transgenic mice. | [116] |
Clinical trial NCT05105958 (ongoing). | ||||
Lithium | Clinical studies (completed) | Pilot study NCT00818389 showed slowing ALS progression. | [108] | |
Combined treatment of lithium and riluzole NCT00818389 did not show any effect | [117] | |||
Unknown | Edaravone | FDA-approved drug in USA Canada and some other countries | Reduced level of oxidative stress and imrpoved motor and respiratory function. | [87] |
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Arslanbaeva, L.; Bisaglia, M. Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment. Molecules 2022, 27, 1471. https://doi.org/10.3390/molecules27051471
Arslanbaeva L, Bisaglia M. Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment. Molecules. 2022; 27(5):1471. https://doi.org/10.3390/molecules27051471
Chicago/Turabian StyleArslanbaeva, Liaisan, and Marco Bisaglia. 2022. "Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment" Molecules 27, no. 5: 1471. https://doi.org/10.3390/molecules27051471
APA StyleArslanbaeva, L., & Bisaglia, M. (2022). Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment. Molecules, 27(5), 1471. https://doi.org/10.3390/molecules27051471