Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia
Abstract
:1. Introduction
2. Vascular Dementia and Oxidative Stress
3. Antioxidant Activity of Repurposed Treatments for the Management of Vascular Dementia
4. Importance of ROS in Alzheimer’s Diseases and Vascular Dementia
5. Primary Reactive Oxygen Species in the Pathogenesis of Vascular Dementia
5.1. Low-Density Lipoprotein, Hydrogen Peroxide, and the Mitochondria
5.2. Peroxynitrite, Nitric Oxide, and Endothelial Cells
5.3. Superoxide and Hydrogen Peroxide, NOX, and the Cerebrovasculature
6. Potential Translational Antioxidant Therapeutics for Vascular Dementia
6.1. Carotenoids
6.2. Idebenone
6.3. Alpha-Lipoic Acid
6.4. Resveratrol
6.5. Selenium
6.6. Curcumin
6.7. Endothelial-Cell-Targted Antioxidants
6.8. Mitochondria-Targeted Antioxidants
6.9. Cerebrovasculature-Targeted Antioxidants
7. Clinical Trials Using Antioxidants for Vascular Dementia
8. Discussion and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
MHPG | 3-methoxy-4-hydroxyphenylglycol |
FeTPPs | 4-sulfonatophenyl porphyrinato iron chloride |
ALA | Alpha-lipoic acid |
AD | Alzheimer’s disease |
Aβ | Amyloid beta |
BCCAO | Bilateral common carotid artery occlusion |
BBB | Blood–brain barrier |
BDNF | Brain-derived neurotrophic factor |
CSF | Cerebral spinal fluid |
CADASIL | Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy |
CARASIL | Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy |
CSF | Cerebral spinal fluid |
CoQ10 | Coenzyme Q10 |
eNOS | Endothelial nitric oxide synthase |
ERK | Extracellular signal-regulated kinase |
GSH | Glutathione |
CA1 | Hippocampal circuit 1 |
HVA | Homovanillic acid |
H2O2 | Hydrogen peroxide |
HIF-1α | Hypoxia inducible factor-1 |
ICAM | Intercellular adhesion molecule 1 |
LDL | Low-density lipoprotein |
MDA | Malondialdehyde |
MMP | Matrix metalloproteinase |
MitoQ | Mitoquinone mesylate |
MWM | Morris water maze |
NADPH | Nicotinamide adenine dinucleotide phosphate |
NO | Nitric oxide |
NFkB/NF-κB | Nuclear factor kappa light chain enhancer of activated B cells |
Ox-LDL | Oxidized LDL |
ONOO− | Peroxynitrite |
ROS | Reactive oxygen species |
RSVL | Reservatrol |
5-HIAA | Serotonin |
SNP | Single-nucelotide polymorphism |
SDH | Succinate dehydrogenase |
O2− | Superoxide |
SOD | Superoxide dismutase |
BH4 | Tetrahydrobiopterin |
UCCAO | Unilateral common carotid artery occlusion |
VCAM-1 | Vascular cell adhesion molecules |
VaD | Vascular dementia |
RSVL | Resveratrol |
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Compound | Mechanism of Action | Effect | Side Effects | Inhibition % (DPPH) | Concentration Range (µg/mL) | Bioavailability | References | |
---|---|---|---|---|---|---|---|---|
Repurposed Medications | Donepezil | AChEi | Mental clarity | Nausea, vomiting, and QT prolongation | 33.5–42.3% | 10–1000 | Moderate (40–100%) | Vinay Munishamappa et al., 2018 [32] |
Galantamine | AChEi | Mental clarity | Dry mouth, constipation, and QT prolongation | 20–35% | 50–200 | High (90%) | Victor Wagner Barajas-Carrillo et al., 2020 [33] | |
Memantine | NMDAr antagonist | Neuronal protection | Dizziness, headache | 1–4% | 100–1000 | High (100%) | I.G. Stankova et al., 2020 [34] | |
Antioxidant Vitamins and Supplements * | Curcumin * | Antioxidant/Anti-inflammatory | Anti-inflammatory | Gastrointestinal upset | 65–75% | 100–500 | Very low (<1%) | Moeka Yamauchi et al., 2024 [35] |
Vitamin C * | Antioxidant | Immune support | Diarrhea (high doses) | 90% | 50–100 | High (70–90%) | Moeka Yamauchi et al., 2024 [35] | |
Vitamin E * | Antioxidant | Skin health | Bleeding risk (high doses) | 70–80% | 100–200 | Low (20–40%) | Moeka Yamauchi et al., 2024 [35] | |
Glutathione * | Antioxidant/Detoxifier | Detoxification | Rare (allergic reactions) | 50–60% | 100–500 | Low (poor oral bioavailability) | Moeka Yamauchi et al., 2024 [35] | |
Resveratrol * | Antioxidant | Cardiovascular health | Gastrointestinal upset | 60–70% | 100–200 | Very low (<1%) | Moeka Yamauchi et al., 2024 [35] |
Species | VaD Model | Antioxidant | Dose | Results | Reference | |
---|---|---|---|---|---|---|
Increase | Decrease | |||||
Human | VaD brain tissue | (r)-ALA | 1 µM, 10 µM, 100 µM, 1 mM, and 10 mM | PDHc activity (10 µm) SDH activity (1 mM) | PDHc activity (10 mM) SDH activity (10 mM) | L. Frolich et al., 2004 [97] |
Human | VaD brain tissue | (s)-ALA | 1 µM, 10 µM, 100 µM, 1 mM, and 10 mM | SDH activity (1 mM) | PDHc activity (10 mM) SDH activity (10 mM) | L. Frolich et al., 2004 [97] |
Male wistar rat adult | Induced diabetic VaD | RSVL | 20 mg/kg i.p. daily for 4 weeks | Cognition, body weight, blood glucose, carbachol, antioxidant levels, BDNF, and eNOS | Inflammation, HO-1, and NOX | Semil Selcen Gocmez et al., 2019 [98] |
Male wistar rat adult | BCCAO | ALA | 50 mg/kg i.p. daily for 28 days | Cognition, GSH levels, ACh, and ChAT | ROS and AChE levels | Ran-ran Zhao et al., 2015 [99] |
Male SD rat 2 mo | BCCAO | RSVL | 20 and 10 mL/kg i.p. daily for 4 weeks | Cognition and SOD levels | MDA and apoptosis | Yeqing Zhang et al., 2019 [100] |
Male SD rat | Induced diabetic VaD | Beta-carotene | 50 mg/kg oral daily for 15 days | Cognition and GSH levels | AChE and thiobarbituric acid reactive substance levels | Khian Giap Lim et al., 2022 [101] |
Male SD rat | Induced diabetic VaD | Beta-carotene | 100 mg/kg oral daily for 15 days | Cognition and GSH levels | AChE and Thiobarbituric acid reactive substances levels | Khian Giap Lim et al., 2022 [101] |
Female SD rat 2 mo | BCCAO | Lycopene | 50 mg/kg i.g. every other day for 2 mo | ROS in CA1, CA3, and DG | −−− | Ning-Wei Zhu et al., 2020 [102] |
Female SD rat 2 mo | BCCAO | Lycopene | 100 mg/kg i.g. every other day for 2 mo | Cognition and SOD activity | ROS in CA1, CA3, and DG | Ning-Wei Zhu et al., 2020 [102] |
Female SD rat 2 mo | BCCAO | Lycopene | 200 mg/kg i.g. every other day for 2 mo | ROS in CA1, CA3, and DG | −−− | Ning-Wei Zhu et al., 2020 [102] |
Gerbil | BCCAO | Lycopene | 20 mg/kg twice a day for 28 days | Cognition, neurons in CA1, and antioxidant activity | Inflammation, apoptosis, and GFAP in CA1 | Wei Chen et al., 2021 [103] |
Male SD rat 7–10 weeks | BCCAO | Lutein | 0.5 mg/kg daily for 30 days | Cognition, pyramidal neuronal cells, and conduction in CA1 | MDA levels | Hamideh Asadi Nejad et al., 2024 [104] |
Male SD rat 7–10 weeks | BCCAO | Lutein | 5 mg/kg | Cognition (NOR), pyramidal neuronal cells, and plasticity in CA1 | MDA levels | Hamideh Asadi Nejad et al., 2024 [104] |
Male mice | UCCAO | Astaxanthin | 50 mg/kg daily for 30 days | Cognition (NOR), SOD levels, and IL-4 levels | IL1β levels | Ningwei Zhu et al., 2020 [105] |
Male mice | UCCAO | Astaxanthin | 100 mg/kg daily for 30 days | Cognition (NOR), IL4, and SOD levels | IL1β and MDA levels | Ningwei Zhu et al., 2020 [105] |
Male mice | UCCAO | Astaxanthin | 200 mg/kg daily for 30 days | Cognition (NOR and MWM), IL4, and SOD levels | IL1β and MDA levels | Ningwei Zhu et al., 2020 [105] |
Male SD rat adult | BCCAO | Idebenone | 100 mg/kg oral daily for 3 weeks | Cognition and neuronal levels in CA1 | TNFα | Xudong Qian et al., 2021 [106] |
Wistar rat 12–14 mo | BCCAO | RSVL | 25 mg/kg oral for 4 weeks | Cognition, neurons, and antioxidant activity | Inflammation and MDA levels | Xingrong Ma et al., 2013 [107] |
Male SD rat | BCCAO | RSVL | 10 mg/kg oral daily for 4 weeks | Cognition, redox ratio, and SOD, HO1, and Nrf2 levels | ROS, GSSG, Hif1α, LPO, and protein carbonylation | Aarti Yadav et al., 2018 [108] |
Male wistar rat | BCCAS | RSVL | 40 mg/kg i.p. for 4 weeks | Cognition, synaptic spines, and synapse-associated proteins | −−− | Huagang Li et al., 2016 [109] |
Female wistar rat 8–10 mo | mBCCAO | RSVL | Daily 10 mg/kg oral for 15 days | GSH and pyramidal neurons | MDA and GFAP levels | Veysel Haktan Ozacmak et al., 2016 [110] |
Male SD rat | BCCAO | RSVL | 50 mg/kg i.g. daily for 9 weeks | Cognition and antioxidant activity | AKT/mTOR signaling pathway, autophagy, apoptosis, and MDA levels | Nan Wang et al., 2019 [111] |
Male wistar rat 3 mo | m2VO | RSVL | 20 mg/kg i.p. daily for 7 days | Cognition, neuronal levels, and NGF | −−− | Janine R Anastacio et al., 2014 [112] |
Male wistar rat | BCCAO | RSVL | 10 mg/kg for 4 weeks | −−− | MDA, TNFα, and nitrite levels | Dongfang Shen et al., 2017 [113] |
Male wistar rat | BCCAO | RSVL | 20 mg/kg for 4 weeks | Cognition and GSH | MDA, IL1β,TNFα, AChE activity, and nitrite levels | Dongfang Shenet al., 2017 [113] |
Male SD rat | BCCAO | Selenium | 0.1 mg/kg p.o. daily for 4 mo | Cognition, posterior cerebral blood flow, neurons, synaptic plasticity, and GSH, NO, and SOD levels | ROS, NOX, and MDA level | Mo-li Zhu et al., 2023 [114] |
Male ICR mice | UCCAO | Curcumin | 20 µmol/kg i.g. daily for 2 weeks | Cognition (MWM) and GSH | ROS, SOD, and MDA levels | Runfang Zhang et al., 2021 [115] |
Male ICR mice | UCCAO | Cur20 | 20 µmol/kg i.g. daily for 2 weeks | Cognition (MWM), GSH, and Hif1α | ROS, SOD, and MDA levels | Runfang Zhang et al., 2021 [115] |
Male SD rats | Induced diabetic VaD | Curcumin | 50 mg/kg i.p. every other day for 8 weeks | Cognition (MWM), NeuN, IL10, and IL4 | Inflammation and apoptosis | Yaling Zheng et al., 2021 [116] |
Antioxidant | Treatment | Study details | Inference | Reference |
---|---|---|---|---|
Idebenone | 45 mg/day b.i.d., for 120 days of oral administration | Randomized double-blind, placebo-controlled, and multicenter study on 108 elderly patients with mild-to-moderate mental deterioration of vascular origin |
Improved acquisition and retention of verbal stimuli; improvements in memory, attention, and cognitive function | Vicenzo Marigliano et al., 1992 [127] |
Idebenone and butyphthalide | Butyphthalide (0.2 g/time; 3 times/day) combined with idebenone (30 mg/time; 3 times/day) for 12 weeks | Retrospective clinical study of 126 patients with vascular dementia, average age of 67.3 ± 7.0 years | Improved daily living activities and cognitive function of patients | Hongxia Zhang et al., 2024 [169] |
Idebenone and butyphthalide | −−− | Randomized observational study on 88 VaD patients | Combination of Butyphthalide with idebenone reduced serum inflammatory mediators levels in VaD patients, improved vascular endothelial functions and cognitive function | Fan Xing Qi et al., 2020 [170] |
Huperzine A | Huperzine A (0.1 mg b.i.d.), 12 consecutive weeks | Randomized, double-blinded, and placebo-controlled study with 78 patients with mild-to-moderate VaD | Improved the cognitive function in patients with VaD | Zhi Qiang Xu et al., 2012 [171] |
Idebenone | 45 mg b.i.d. orally (90 mg over 6 mo) | Open multicenter study | Improved cognitive function in patients with VaD (MID and CCVD) | Giuseppe Nappi et al., 1992 [172] |
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White, A.L.; Talkington, G.M.; Ouvrier, B.; Ismael, S.; Solch-Ottaiano, R.J.; Bix, G. Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia. Biomolecules 2025, 15, 6. https://doi.org/10.3390/biom15010006
White AL, Talkington GM, Ouvrier B, Ismael S, Solch-Ottaiano RJ, Bix G. Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia. Biomolecules. 2025; 15(1):6. https://doi.org/10.3390/biom15010006
Chicago/Turabian StyleWhite, Amanda Louise, Grant M. Talkington, Blake Ouvrier, Saifudeen Ismael, Rebecca J. Solch-Ottaiano, and Gregory Bix. 2025. "Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia" Biomolecules 15, no. 1: 6. https://doi.org/10.3390/biom15010006
APA StyleWhite, A. L., Talkington, G. M., Ouvrier, B., Ismael, S., Solch-Ottaiano, R. J., & Bix, G. (2025). Reactive Oxygen Species, a Potential Therapeutic Target for Vascular Dementia. Biomolecules, 15(1), 6. https://doi.org/10.3390/biom15010006