Antioxidant and Anti-Inflammatory Defenses in Huntington’s Disease: Roles of NRF2 and PGC-1α, and Therapeutic Strategies
Abstract
:1. Introduction
2. HD Pathogenesis
2.1. Oxidative Stress and Mitochondrial Dysfunction
2.2. Neuroinflammation
3. Role of NRF2 and PGC1α
3.1. NRF2
3.2. PGC-1α
3.3. Interaction Between NRF2 and PGC-1α
4. Antioxidant Therapeutic Strategies Involving NRF2 and PGC-1α Signaling
4.1. Modulation of NRF2 as a Therapy for HD
Therapeutic Strategy | HD Model | NRF2 Activation | PGC-1α Activation | Effects | Ref. |
---|---|---|---|---|---|
Naringin | 3-NPA-stressed rats | V | Reduced neuroinflammatory markers and oxidative damage | [97] | |
3-NPA-stressed PC12 cells | V | Reduced 3-NPA-induced neurotoxicity | [53] | ||
Protopanaxatriol | 3-NPA-stressed rats | V | Reduced neuronal injury | [98] | |
6-Shogaol | 3-NPA-stressed rats | V | Improved behavior and biochemical indices with restored levels of neurotransmitters and decreased neuroinflammatory molecules | [99] | |
CDDO-MA | 3-NPA-stressed rats | V | Reduced neuronal injury | [101] | |
CDDO-EA | N171-82Q mice | V | Improved motor performance and increased neuronal survival in striatum | [95] | |
CDDO-TFA | N171-82Q mice | V | Improved motor performance and increased neuronal survival in striatum | [95] | |
Azilsartan | 3-NPA-stressed rats | V | Improved motor function, restored neurotransmitter balance, and reduced inflammation, oxidative stress, and apoptosis | [103] | |
Cysteamine | Mouse primary neurons and human iPSCs | V | Reduced oxidative stress and neuroprotection | [104] | |
Human patients | V | (Ongoing study) | NCT02101957 | ||
DMF | YAC128 and R6/2 mice | V | Improvements in muscle function, stabilization of body weight, and a marked reduction in neuronal loss | [9] | |
Resveratrol | Human patients | V | (Unpublished results) | NCT02336633 | |
Striatal and cortical neurons from YAC128 mice, Human lymphoblasts, and YAC128 mice | V | Rescued mitochondrial membrane potential and respiratory activity with TFAM upregulation | [111] | ||
EGCG | Human patients | V | (Unpublished results) | NCT01357681 | |
PGC-1α overexpression | N171-82Q mice | V | Improved neurological function and TFEB-mediated eradication of mHtt aggregates in the brain | [80] | |
R6/2 mice | V | Halted striatal degeneration | [112] | ||
Fenofibrate | 3-NPA-stressed rats | V | PPARγ-mediated enhanced mitochondrial oxidative phosphorylation and biogenesis. | [113] | |
Human patients | V | Improved motor and cognitive symptoms | NCT03515213 | ||
Rolipram | Quinolinic acid-stressed rats | V | Antidepressant and neuroprotective effects | [114] | |
R6/2 mice | V | Neuroprotective effects | [115] | ||
R6/2 mice | V | Improved motor functions and neuroprotection | [116] | ||
GSK356278 | Human patients | V | Able to reach the brain | NCT01602900 | |
SIRT1 overexpression | N171-82Q mice | V | Improved metabolism and neuroprotection, decreased brain atrophy | [117] | |
R6/2 mice | V | Improves survival, neuropathology and neurotrophins levels | [118] | ||
Viniferin | Striatal cells and primary cortical neurons from HD mice, N63-148Q PC12, and N2A cells | V | SIRT3-dependent neuroprotection | [119] | |
Rosiglitazone | Striatal cells from HD mice | V | Reduced mitochondrial dysfunction and oxidative stress | [120] | |
Benzafibrate | R6/2 mice | V | Improved behavior and survival, decreased striatal atrophy and oxidative stress | [121] |
4.2. Modulation of PGC-1α as a Therapy for HD
5. Discussion
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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D’Egidio, F.; Qosja, E.; Ammannito, F.; Topi, S.; d’Angelo, M.; Cimini, A.; Castelli, V. Antioxidant and Anti-Inflammatory Defenses in Huntington’s Disease: Roles of NRF2 and PGC-1α, and Therapeutic Strategies. Life 2025, 15, 577. https://doi.org/10.3390/life15040577
D’Egidio F, Qosja E, Ammannito F, Topi S, d’Angelo M, Cimini A, Castelli V. Antioxidant and Anti-Inflammatory Defenses in Huntington’s Disease: Roles of NRF2 and PGC-1α, and Therapeutic Strategies. Life. 2025; 15(4):577. https://doi.org/10.3390/life15040577
Chicago/Turabian StyleD’Egidio, Francesco, Elvira Qosja, Fabrizio Ammannito, Skender Topi, Michele d’Angelo, Annamaria Cimini, and Vanessa Castelli. 2025. "Antioxidant and Anti-Inflammatory Defenses in Huntington’s Disease: Roles of NRF2 and PGC-1α, and Therapeutic Strategies" Life 15, no. 4: 577. https://doi.org/10.3390/life15040577
APA StyleD’Egidio, F., Qosja, E., Ammannito, F., Topi, S., d’Angelo, M., Cimini, A., & Castelli, V. (2025). Antioxidant and Anti-Inflammatory Defenses in Huntington’s Disease: Roles of NRF2 and PGC-1α, and Therapeutic Strategies. Life, 15(4), 577. https://doi.org/10.3390/life15040577