Targeting Ferroptosis in Parkinson’s: Repurposing Diabetes Drugs as a Promising Treatment
Abstract
1. Introduction
2. Antidiabetic Drugs for Parkinson’s Disease
2.1. Metformin
2.2. Incretins and Incretin Mimetics
2.2.1. Preclinical Evidence for GIP and GLP-1R Agonists Usage in Parkinson’s Disease Treatment
2.2.2. Clinical Evidence for GIP and GLP-1R Agonists Usage in Parkinson’s Disease Treatment
2.3. DPP-4 Inhibitors (Gliptins)
2.4. Peroxisome-Proliferator-Activated Receptor Gamma (PPAR-γ) Agonists
2.5. Sodium–Glucose Cotransporter-2 Inhibitors (SGLT2i)
2.6. Meglitinides (Glinides)
2.7. Alpha-Glucosidase Inhibitors (AGIs)
2.8. T2D Drugs Which Are/Were in Clinical Trials Repurposing for the Treatment of Parkinson’s Disease
- 1.
- Exenatide
- 2.
- Liraglutide
- 3.
- Pioglitazone
- 4.
- Semaglutide
- 5.
- Lixisenatide
- 6.
- Metformin
3. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Key Mechanism | Details |
---|---|
Reduction of Oxidative Stress | Decrease in ROS Production: Metformin inhibits reverse electron flux through mitochondrial complex I, reducing ROS production and preventing oxidative stress and cell death [50]. Enhancement of Antioxidant Systems: Increases levels of glutathione (GSH) and superoxide dismutase (SOD), enhancing the cell’s ability to neutralize ROS [56,58]. Scavenging Free Radicals: Directly scavenges hydroxyl free radicals and indirectly decreases ROS through NADPH oxidase or the mitochondrial respiratory chain [53,54]. Induction of MnSOD: Promotes manganese-dependent superoxide dismutase (MnSOD) and mitochondrial biogenesis, reducing mitochondrial ROS [51]. |
Enhancement of Autophagy and Protein Homeostasis | Activation of Autophagy Pathways: Enhances autophagy, promoting the elimination of α-syn aggregates, which are neurotoxic in PD [65,66,67]. Reduction of α-syn Aggregation: Decreases α-syn aggregation and dopaminergic neuron loss in PD models [65,67]. Regulation of Protein Phosphorylation: Reduces levels of phosphorylated α-syn at serine 129 by activating protein phosphatase 2A (PP2A) via AMPK-dependent and independent pathways [63,64]. |
Energy Metabolism and Mitochondrial Function | AMPK Activation: Activates AMPK, promoting metabolic balance and neuronal survival. AMPK activation leads to inhibition of lipid biosynthesis and maintenance of ATP levels, crucial for neuronal health [36,37,38,39]. Mitochondrial Protection: Causes mild inhibition of mitochondrial complex I, maintaining ATP production and reducing energy stress. Promotes mitochondrial biogenesis, enhancing mitochondrial function and resilience [30,31,32,33,34,51]. |
Anti-Inflammatory Effects | Reduction of Inflammation: Regulates changes in astrocytes and microglia, reducing neuroinflammation and protecting dopaminergic neurons [73]. |
Protection of Dopaminergic Neurons and Improvement in PD Models | Protective Effects in PD Models: Reduces dopaminergic neuron loss and α-syn accumulation in various PD models [65,67,69]. Enhancement of Motor Functions: Improves motor performance in MPTP-induced PD mice by restoring dopamine levels and reducing pathological markers [65,68]. Reduction of Neurotoxic Aggregates: Prevents MGO-induced α-syn oligomerization, mitigating neurodegeneration [19,66,67]. |
Modulation of Signaling Pathways | Nrf2 Pathway Activation: Activates the Nrf2 signaling pathway, enhancing cellular antioxidant defenses and reducing oxidative damage [56]. AMP-Dependent Pathways: Utilizes alternative AMPK activation routes, such as the lysosomal pathway, stabilizing cellular energy homeostasis and resilience against stress [40]. |
Miscellaneous Neuroprotective Mechanisms | Indirect Effects on Insulin Sensitivity: Enhances insulin sensitivity in peripheral tissues, potentially supporting overall neuronal health through metabolic regulation [25,26]. Scavenging Advanced Glycation End-Products (AGEs): Acts as a scavenger of methylglyoxal (MGO) and may prevent the accumulation of AGEs, reducing neurotoxicity and protein dysfunction [19,66,67,68]. |
Inhibition of Ferroptosis | Modulation of Ferroptosis Markers: Increases GPx4 and suppresses ACSL4 levels, preventing lipid peroxidation and ferroptosis [56,70,71]. Regulation of Iron Homeostasis: Upregulates ferroportin (FPN) expression, reducing iron overload and enhancing iron detoxification. Reduces ferritin heavy chain expression, improving iron homeostasis [59]. Enhancement of Antioxidant Defenses: Elevates GSH levels and SOD activity, strengthening defenses against ferroptosis [58,69]. Inhibition of Lipid Peroxidation: Decreases malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels, reducing markers of lipid peroxidation [55,67]. |
Generic Name/Trade Name | Indication | Approval Year |
---|---|---|
Exenatide (Byetta®) | T2D | 2005 |
Liraglutide (Victoza®) | T2D | 2010 |
Dulaglutide (Trulicity®) | T2D | 2014 |
Liraglutide (Saxenda®) | Obesity/overweight | 2014 |
Lixisenatide (Adlyxin®) | T2D | 2016 |
Liraglutide + insulin degludec (Xultophy®) | T2D | 2016 |
Lixisenatide + insulin glargine (Soliqua®) | T2D | 2016 |
Exenatide extended release (Bydureon®) | T2D | 2017 |
Semaglutide injection (Ozempic®) | T2D | 2017 |
Semaglutide tablets (Rybelsus®) | T2D | 2019 |
Semaglutide (Wegovy®) | Obesity/overweight | 2021 |
Tirzepatide (Mounjaro®) (dual GLP-1/GIP receptor agonist) | T2D | 2022 |
Tirzepatide (Zepbound®) (dual GLP-1/GIP receptor agonist) | Obesity/overweight | 2023 |
Key Effects | Details |
---|---|
Neuroprotective Efficacy and Neuronal Protection | Synaptic Protection and Synaptogenesis: Protects synapses and promotes the formation of new synapses, enhancing neural connectivity [99]. Enhancement of Synaptic Plasticity: Improves the adaptability of synapses, facilitating learning and memory consolidation [99]. Rescue of Cognitive Decline: Prevents or reverses deterioration in cognitive functions [90,94]. Regulation of Glial Cell Functions: Modulates microglia and astrocyte activation, reducing neuroinflammation [112,113,114]. Prevention of Ca2⁺ Overload: Protects neurons from calcium-induced toxicity [99]. Protection of Nigrostriatal Neurons: Safeguards dopaminergic neurons in the nigrostriatal pathway [100,101,102]. Dopamine Replenishing: Restores dopamine levels in the brain, improving motor functions [100,101,102]. |
Stress and Inflammation Reduction, Anti-Apoptotic Effects | Suppression of ER Stress: Reduces endoplasmic reticulum stress, preventing protein misfolding and aggregation [104,107]. Anti-Inflammatory Effects: Decreases neuroinflammation by reducing pro-inflammatory cytokines [87,112,113,114,126]. Protection from External Oxidative Stress: Mitigates damage caused by oxidative agents [99,100,101,102,104,107]. Anti-Apoptotic Activities: Prevents programmed cell death in neurons [112,113,114]. |
Mitochondrial Protection | Mitigation of Mitochondrial Dysfunction: Improves mitochondrial integrity and function, ensuring efficient energy production [110]. Recovery of Mitochondrial Function: Restores normal mitochondrial operations, preventing energy deficits [110]. Reduction of Superoxide Formation: Decreases superoxide radical production, preventing oxidative mitochondrial damage [126,127,128,129]. |
Ferroptosis Inhibition | Reduction of Iron Overload: Decreases iron accumulation in the brain and other tissues, preventing iron-induced oxidative damage [94,107,125,126,127,128,129,131]. Modulation of Ferroptosis Markers: Increases GPx4 and SLC7A11 expression, and decreases ACSL4 levels, thereby inhibiting ferroptosis [110]. Enhancement of Antioxidant Defenses: Elevates GSH and SOD levels, strengthening cellular defenses against ferroptosis [107,108,126,127,128,129,130,131]. Activation of Antioxidant Signaling Pathways: Activates the Nrf2/HO-1 pathway, enhancing overall antioxidant capacity [107,126]. Regulation of Antioxidant Proteins: Increases Bcl-2 and Bcl-xL, which scavenge free radicals and inhibit superoxide anion formation [111]. Reduction of Lipid Peroxidation: Lowers MDA and HNE levels, reducing markers of lipid peroxidation [99,108,131]. |
Improvement in Motor and Cognitive Functions | Enhanced Motor Performance: Improves motor functions in PD models and patients through dopamine replenishing and neuronal protection [115,116,117,118,119,120,121]. Cognitive Function Improvement: Enhances cognitive capabilities and reduces cognitive decline through synaptic and neuronal support [90,94,99,120,126,127,128,129,130,131]. |
Iron Metabolism Regulation | Reduction of Iron Overload in Tissues: Lowers iron levels in the liver and brain, preventing iron-induced oxidative stress [94,107,131]. Upregulation of Iron Exporters: Increases ferroportin (FPN) expression and decreases transferrin receptor (TfR1) expression, improving iron homeostasis and reducing iron import [107,128,129,130,131]. |
Neurogenesis Enhancement | Promotion of Adult Neurogenesis: Encourages the formation of new neurons in the adult brain, particularly in the hippocampus [90,94]. Increase in Neuronal Progenitor Cells: Boosts the population of neuronal progenitor cells, aiding in neuronal regeneration [94]. |
Oxidative Stress Reduction | Scavenging of Free Radicals: Directly scavenges hydroxyl radicals and indirectly reduces ROS production through DPP-4 and mitochondrial pathways [52,53,55,87]. Upregulation of Antioxidant Enzymes: Increases the expression of MnSOD, GPx4, and other antioxidant enzymes, enhancing the cellular capacity to neutralize ROS [107,108,126,127,128,129,130,131]. |
Protection against Dopaminergic Neuron Loss | Reduction of α-Synuclein Aggregation: Prevents the accumulation of toxic α-syn oligomers, mitigating their neurotoxic effects [99,112,113,114,131]. Protection from Dopaminergic Neuron Degeneration: Safeguards neurons that produce dopamine, reducing neuron loss and improving motor functions [100,101,120,121,122,123,124,125,126,127,128,129,130,131]. |
Generic Name/Trade Name | Approved by | Approval Year |
---|---|---|
Sitagliptin (Januvia) | FDA | 2006 |
Vildagliptin (Galvus) | EU | 2007 |
Saxagliptin (Onglyza) | FDA | 2009 |
Linagliptin (Tradjenta) | FDA | 2011 |
Gemigliptin (Zemiglo) | Korea | 2012 |
Anagliptin (Suiny) | Japan | 2012 |
Teneligliptin (Tenelia) | Japan | 2012 |
Alogliptin (Nesina) | FDA | 2013 |
Trelagliptin (Zafatek/Wedica) | Japan | 2015 |
Omarigliptin (Marizev) | Japan | 2015 |
Sitagliptin (Zituvio) | FDA | 2023 |
Evogliptin (Suganon/Evodine) | Korea | - |
Gosogliptin (Saterex) | Rusia | - |
Key Mechanisms | Details |
---|---|
Neuroprotective Efficacy and Neuronal Protection | Promotes neuronal growth and survival [146] Enhances neurotrophic factors, supporting neuronal health and function [146] Prevents Dopamine Reduction and Dopaminergic Neuron Loss: Protects dopaminergic neurons from degeneration, preserving dopamine levels in the brain [135,145,146]. |
Stress and Inflammation Reduction, Anti-Apoptotic Effects | Downregulation of ER Stress Markers: Reduces ER stress by downregulating CHOP, TRIB3, and activating ATF-4, thereby preventing protein misfolding and apoptosis [141,142,143]. Suppress Inflammatory Pathways: Inhibits inflammatory signaling pathways, reducing the production of pro-inflammatory cytokines [135,145]. Prevention of Apoptosis: Prevents programmed cell death in neurons by reducing oxidative and nitrosative stress [135,145,146]. |
Mitochondrial Protection | Restoring Mitochondrial Complex I Activity and Bcl-2 Levels: Enhances mitochondrial function and integrity, maintaining ATP synthesis and preventing energy deficits [145]. |
Ferroptosis Inhibition | Improvement of Iron Metabolism: Regulates iron-related proteins such as TfR1 and FPN1, reducing iron overload and enhancing iron detoxification [141,143]. Reduction of Oxidative and Nitrosative Stress: Decreases iNOS transcription and MPO activity, inhibiting ROS and RNS production [144,145]. Reduction of lipid peroxidation: Decreases TBARS levels [144] Activation of Antioxidant Signaling Pathways (Nrf2): Enhances antioxidant defenses and reduces lipid peroxidation [135,145]. |
Aspect | Incretin Mimetics | DPP-4 Inhibitors |
---|---|---|
Mechanism of Action | Directly activate GLP-1receptors enhancing insulin secretion and neuroprotection | Inhibit DPP-4 enzyme, increasing endogenous GLP-1 and GIP levels |
Neuroprotective Efficacy | Strong neuroprotective effects through direct activation of GLP-1Rs, promoting neurogenesis, synaptic plasticity, and reducing oxidative stress and inflammation | Moderate neuroprotective effects; primarily reduce inflammation and apoptosis indirectly by increasing GLP-1 levels |
BBB Permeability | Some (e.g., Exenatide, lixisenatide) can cross the BBB, allowing direct central nervous system effects | Generally limited BBB permeability, restricting central effects |
Impact on Ferroptosis-related Pathways | Potential impact on ferroptosis through reducing oxidative stress, improving mitochondrial function, and enhancing antioxidant pathways (e.g., Nfr2/HO-1) | Limited direct evidence on ferroptosis; potential indirect effects through reducing oxidative stress and inflammation |
Clinical Evidence in PD | Demonstrated benefits in motor and cognitive functions in clinical trial; potential disease-modifying effects | Some positive effects in preclinical models; clinical evidence less robust compared to GLP-1RAs |
Combination Therapy Potential | Can be combined with other therapies for enhanced neuroprotective effects | Potential to enhance GLP-1 activity and complement other PD treatments |
Generic Name/Trade Name | Indication | Approval Year |
---|---|---|
Acarbose (Precose®) | T2D | 1995 |
Miglitol (Glyset®) | T2D | 1996 |
Voglibose (Voglib®) | T2D | Only in Japan |
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Duță, C.; Muscurel, C.; Dogaru, C.B.; Stoian, I. Targeting Ferroptosis in Parkinson’s: Repurposing Diabetes Drugs as a Promising Treatment. Int. J. Mol. Sci. 2025, 26, 1516. https://doi.org/10.3390/ijms26041516
Duță C, Muscurel C, Dogaru CB, Stoian I. Targeting Ferroptosis in Parkinson’s: Repurposing Diabetes Drugs as a Promising Treatment. International Journal of Molecular Sciences. 2025; 26(4):1516. https://doi.org/10.3390/ijms26041516
Chicago/Turabian StyleDuță, Carmen, Corina Muscurel, Carmen Beatrice Dogaru, and Irina Stoian. 2025. "Targeting Ferroptosis in Parkinson’s: Repurposing Diabetes Drugs as a Promising Treatment" International Journal of Molecular Sciences 26, no. 4: 1516. https://doi.org/10.3390/ijms26041516
APA StyleDuță, C., Muscurel, C., Dogaru, C. B., & Stoian, I. (2025). Targeting Ferroptosis in Parkinson’s: Repurposing Diabetes Drugs as a Promising Treatment. International Journal of Molecular Sciences, 26(4), 1516. https://doi.org/10.3390/ijms26041516