Targeting Ferroptosis in Parkinson’s Disease: Mechanisms and Emerging Therapeutic Strategies
Abstract
1. Introduction
2. The Role of Ferroptosis in PD Pathogenesis
2.1. α-syn and Ferroptosis
2.2. Oxidative Stress and Ferroptosis
2.3. Mitochondrial Dysfunction and Ferroptosis
2.4. Microglia Associated Neuroinflammation and Ferroptosis
2.5. NM Accumulation and Ferroptosis
3. Therapeutic Approaches Targeting Ferroptosis in PD
3.1. Decreasing Intracellular Iron Load
3.1.1. Simple Iron Chelators
3.1.2. Iron Chelators with Multi-Dimensional Function
Hydroxyquinoline
Clioquinol
Flavonoids
3.1.3. Other Iron Metabolism-Related Drugs
Drugs | Inducer/Cell or Animal Models | Pharmacology | Mechanism | Reference |
---|---|---|---|---|
DFO | MPTP/mice | ↓motor deficiency ↑TH positive neurons ↓iron-positive cells in SN and striatum | iron chelation ↓α-syn, DMT1, TFR | [61,64] |
DFP | MPTP/mice | ↑GSH ↓MDA ↓8-oxodeoxyguanosine ↑dopamine in striatum | iron chelation ↓unstable LIP in mitochondria | [64] |
Transferrin | MPTP/mice | ↓motor deficiency | iron chelation | [66] |
PBT434 | 6-OHDA/mice MPTP/mice Transgenic mice(hA35T α-syn) | ↓neurons loss in SN ↓oxidative damage markers | iron chelation ↓α-syn in SN ↑FPN1 ↑DJ-1 | [67] |
VK-28 | 6-OHDA/rats | ↓neurotoxicity ↑dopaminergic neurons | iron chelation | [69] |
M30 | Lactacystin/mice | ↓dopaminergic neurons loss | iron chelation ↓MAO-A, MAO-B non-selectively ↑bcl-2 levels ↓microglial activation ↓proteasome inhibition | [70] |
HLA20 | 6-OHDA/P19 | neuroprotection | iron chelation ↓MAO-B selectively | [68] |
CQ | MPTP/monkeys | ↓iron in SN ↓ROS ↓4-HNE ↑serum SOD ↑GSH↓MDA | Iron chelator ↑FPN1 ↓TFR2 ↑AKT/mTOR ↓p53-mediated cell death | [73] |
Curcumin | 6-OHDA/rats | ↑dopamine in striatum ↑TH positive neurons in striatum ↓iron-stained cells | iron chelation | [74] |
Baicalein | Vitamin K/SK-N-MC | ↓iron content ↓ROS ↓MDA | iron chelation ↓Bax ↓caspase-9 ↑bcl-2 | [75] |
MPTP/mice | ↓motor deficiency ↑dopaminergic neurons | iron chelation ↓nuclear shift of NF-κB | [76] | |
SN4741 cells | ↓α-syn transmission | covalently bound to α-syn | [77] | |
Apoferritin | MPTP/mice | ↓LIP | ↓DMT1, ACSL4 ↑FSP1 | [78] |
Iron carbonyl | Retenone/rat | Control iron utilization | ↓IRP1 ↑ACO1 | [79] |
miR-335 | 6-OHDA/rats 6-OHDA/PC12 | ↑LIP | ↓FTH1 | [80] |
miR-221 | MPP+/SH-SY5Y | ↓LIP | ↓TFR2 | [81] |
3.2. Decreasing LPO Generation
3.2.1. Radical Trapping Antioxidants (RTAs)
3.2.2. ACSL4 Inhibitor
3.2.3. LPCAT3 Inhibitor
3.2.4. ALOX5 Inhibitor
3.2.5. PUFAs Inhibitor
3.2.6. iPLA2β-Related Drugs
Drugs | Inducer/Cell or Animal Models | Pharmacology | Mechanism | Reference |
---|---|---|---|---|
CuII(astm) | RSL3/mice cortical neurons | ↓LPO | RTA | [87] |
Fer-1 | Glutamate/HT-22 | ↑GPX4 ↓MDA ↑SOD ↓ROS ↓LPO | RTA ↑Nrf2/GPX4 | [45] |
TEMPO | Glutamate/mouse hippocampal cell lines | ↓LPO ↓cell death | RTA | [89] |
AS | RSL3/HT22 | ↓LPO | ↓ACSL4 | [100] |
Calusenamide | MPTP/mice | ↓LPO | ↓ALOX5 activation/nuclear translocation | [103] |
Licofelone | MPTP/mice | ↑locomotor ability | ↓ALOX5 | [104] |
D-PUFAs | Mixed cultures of cortical neurons of rats | ↓α-syn-induced LPO and α-syn-induced cell death | compete with PUFAs | [105,106] |
DHA | PLA2G6D331Y/D331Y mice | Improve motor deficits ↓neuroinflammation | ↓LPO | [109] |
Azoramide | PLA2G6D331Y dopaminergic neurons | Improve DA damage | ↑ER function ↑CREB signaling | [107] |
3.3. Regulating Antioxidant Pathway
3.3.1. Regulating System Xc−-GPX4/GSH Pathway
3.3.2. Regulating Nrf2-Related Pathway
3.3.3. Regulating FSP1/CoQ10 Pathway
3.3.4. Multifunctional Antioxidant Regulator
Drugs | Inducer/Cell or Animal Models | Pharmacology | Mechanism | Reference |
---|---|---|---|---|
Trx-1 | MPP+/PC12 MPP+/SH-SY5Y MPTP/mice | ↑GSH | ↑GPX4 | [117] |
TFA | MPTP/mice | ↑GSH | ↑SLC7A11/GPX4 | [118] |
α-LA | MPP+/PC12 | ↓MDA, 4-HNE, iron, ROS | ↑PI3K/Akr/Nrf2/ SLC7A11/GPX4 | [129] |
6-OHDA/PC12 | ↓iron, LPO ↓mitochondrial damage | ↑SIRT1/Nrf2/ FTH1/GPX4 | [130] | |
Fer-1 | Glutamate/HT-22 | ↓MDA ↑SOD ↓ROS ↓LPO | RTA ↑Nrf2/GPX4 | [45] |
ACT | MPP+/SH-SY5Y MPTP/mice | ↑mitochondrial integrity in dopaminergic neurons ↓LPO | ↑Nrf2-mitophagy | [132] |
WA | MPTP/mice | ↓loss of dopaminergic neurons ↓neuroinflammation ↓movement disorder | ↑DJ1/Nrf2 while ↓STING | [35,133] |
CoQ10 | MPTP/mice | ↑survival of dopaminergic neurons and TH positive neurons ↓α-syn aggregation | ↑CoQ10 | [138] |
Idebenone | rotenone/rats | ↓movement disorder ↑survival of TH positive neurons | ↑GPX4 ↑NAD(P)H dihydrogenase [quinone]-1 | [46] |
MPTP/mice | improve PD symptoms | ↑Parkin/PINK1 mitophagy | [143] | |
DPT3f | Ischemic stroke | ↑CoQ10 | ↑FSP1/CoQ10 | [144] |
Novel Probiotic L. lactis MG1363-pMG36e-GLP-1 | MPTP/mice | Neurotrophy ↑CoQ10 ↓LPO ↓α-syn ↑TH positive nerve cells ↑BBB integrity ↑intestinal barrier reverse dysbacteriosis | ↑Keap1/Nrf2/GPX4 ↑FSP1/CoQ10 ↓ACSL4 | [101] |
4. Conclusions
5. Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Zhou, M.; Xu, K.; Ge, J.; Luo, X.; Wu, M.; Wang, N.; Zeng, J. Targeting Ferroptosis in Parkinson’s Disease: Mechanisms and Emerging Therapeutic Strategies. Int. J. Mol. Sci. 2024, 25, 13042. https://doi.org/10.3390/ijms252313042
Zhou M, Xu K, Ge J, Luo X, Wu M, Wang N, Zeng J. Targeting Ferroptosis in Parkinson’s Disease: Mechanisms and Emerging Therapeutic Strategies. International Journal of Molecular Sciences. 2024; 25(23):13042. https://doi.org/10.3390/ijms252313042
Chicago/Turabian StyleZhou, Minghao, Keyang Xu, Jianxian Ge, Xingnian Luo, Mengyao Wu, Ning Wang, and Jianfeng Zeng. 2024. "Targeting Ferroptosis in Parkinson’s Disease: Mechanisms and Emerging Therapeutic Strategies" International Journal of Molecular Sciences 25, no. 23: 13042. https://doi.org/10.3390/ijms252313042
APA StyleZhou, M., Xu, K., Ge, J., Luo, X., Wu, M., Wang, N., & Zeng, J. (2024). Targeting Ferroptosis in Parkinson’s Disease: Mechanisms and Emerging Therapeutic Strategies. International Journal of Molecular Sciences, 25(23), 13042. https://doi.org/10.3390/ijms252313042