Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies
Abstract
:1. Introduction
2. Cerebral Small Vessel Disease
3. Risk Factors
3.1. Genetic Factors
3.2. Traditional Factors (Co-Morbid)
3.3. Environmental Factors
4. Neuroimaging Characteristics of Small Vessels Disease (SVD)
5. Role of Heavy Metals in CSVD
5.1. Lead (Pb)
5.2. Copper (Cu)
5.3. Mercury (Hg)
5.4. Arsenic (As)
5.5. Cadmium (Cd)
6. Molecular Mechanisms
6.1. Oxidative Stress
6.2. Inflammation
6.3. MMPs Expression
7. Role of Cellular Antioxidant Enzymes to Combat Metal-Induced CSVD
8. Therapeutic Strategies
9. Possible Measures to Avoid Heavy Metals Exposure
- Controls of the heavy metal level in the water and food [278];
- Alternatives to dental amalgam;
- Alternative use of heavy metal-based agrochemicals such as copper oxychloride;
- Alternative use of copper plumbing;
- Stop smoking because cigarette smoke contains cadmium that can be absorbed through the lungs [279];
- Pay attention to local fish advisories regarding mercury levels and also try to limit your consumption of larger fish because they live long and absorb more mercury from the sea [280];
- Wear masks and protective clothing to avoid occupational exposure [281].
10. Conclusions and Future Direction
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
As | Arsenic |
ATP | Adenosine triphosphate |
CAA | Cerebral amyloid angiopathy |
CAT | Catalase |
Cd | Cadmium |
CNS | Central Nervous System |
CSVD | Cerebral Small Vessel Disease |
CTR1 | High-affinity copper uptake protein 1 |
CVD | Cardiovascular disease |
Cu | Copper |
DMSA | 2,3-dimercaptosuccinic acid |
DNA | Deoxyribonucleic acid |
EC | Endothelial cells |
EDTA | Ethylenediaminetetraacetic acid, |
GPx | Glutathione Peroxidase |
GSH | Glutathione |
Hg | Mercury |
H2O2 | Hydrogen Peroxide |
IL | Interleukin |
IkK | IκB kinase |
MDA | Malondialdehyde |
MeHg | Methyl mercury |
MMPs | Matrix metalloproteinase |
NADPH | Nicotinamide adenine dinucleotide phosphate |
NF-κB | Nuclear factor-kappa B3 |
NO | Nitric oxide |
Pb | Lead |
ROS | Reactive oxygen species |
SD rat | Sprague Dawley |
SOD | Super Oxide Dismutase |
TNF-α | Tumor necrosis factor-α |
TTM | Tetrathiomolybdate |
VEGF | Vascular endothelial growth factor |
WD | Wilsons Disease |
eNOS | Endothelial nitric oxide synthase |
hCMEC/D3 | Human brain microvascular endothelial cells |
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System | Concentration | Exposure Duration | Toxicity | Ref. |
---|---|---|---|---|
In-vitro (hCMEC/D3 Cell line | 25–200 µM Pb | 48 h |
| [67] |
In-vivo male Wistar rats | 200 mg/L lead acetate Drinking water | 3 Months |
| [75] |
In-vitro RBE4 cell line | 10−5 M and 10−6 M lead acetate at | 2 h, 4 h, 8 h, 16 h, and 24 h |
| [76] |
In-vitro epithelial Z310 cells | 5 and 10 μM Pb | Pre and post exposure |
| [77] |
In-vivo Sprague-Dawley dams | 4% lead carbonate via feed | 5, 10, 15 days |
| [78] |
In-vivo Male SD rats | 100, 200, 300 PPM/mL Drinking water | eight weeks |
| [79] |
In-vivo Male SD rats | 50 mg/kg Pb acetate i.p., injection | 24 h |
| [80] |
Primary culture brain microvessels isolated from 6-day-old rat pups | 1 μM lead | 0–60 min |
| [81] |
In vitro C6 glia cells and ECV304 | 2.5, 5, 10 μM Pb | 6, 12, 24, 48 h |
| [82] |
In- vivo Male Sprague–Dawley rats | 342 μg Pb/mL as Pb acetate | Once every other day 6 weeks |
| [83] |
System | Concentration | Exposure Duration | Toxicity | Ref. |
---|---|---|---|---|
In-vitro rBMECs cells | 1.5–50 μg/mL (Cu nanoparticles) | 0–8 h |
| [94] |
Primary culture (SPF Wistar neonate rats) Brain microvascular endothelial cells (BMECS) | 30–300 μM (Cucl2) | 12 h |
| [100] |
In-vitro HUVEC, HMEC-L, and HIAEC cells | 10 to 50 μM (Cucl2) | 12 h |
| [101] |
In-vivo Sprague Dawley rats | IP 50 mg/kg IV 30 mg/kg Cortical superfusion (20 µg/10 µL) (Cu nanoparticles) | 24 h |
| [102] |
AD patients | - | - |
| [103] |
In-vivo C57BL6 mice | 1 mg/L (Cucl2 + cholesterol As a risk factor) Drinking water | 4 weeks |
| [104] |
In-vivo 3xTg-AD | 250 ppm Cu sulfate (CuSO4) Drinking water | 3 or 9 months |
| [105] |
In-vivo Male Wistar rats | 10 µg/mL (Cucl2) | 1 h |
| [106] |
In- vitro Bovine aortic endothelial cells (BAECs) | 0–500 μg/mL Cu2O | 12 h |
| [107] |
In- vitro human aortic endothelial cells (HAECs) | 100 μM Cupric sulfate | 0–16 h |
| [108] |
System | Concentration | Exposure Duration | Toxicity | Ref. |
---|---|---|---|---|
In-vivo normotensive Wistar rats | HgCl2 (first dose 4.6 μg/kg, subsequent dose 0.07 μg/kg/day, im to cover daily loss) | 30 days |
| [115] |
In-vitro HUVECs | (1.0–5.0 microM) MeHg | 24 h |
| [125] |
In-vitro Human brain micro-vascular cells | (1, 2, 3 µM MeHg) (2 µM HgCl2) | 24 h |
| [117] |
In-vivo male Wistar rats | 20-ppm MeHg Drinking water | 4 weeks |
| [126] |
In-vivo Sprague-Dawley rats | 1.0 mg/kg Mercuric bichloride Subcutaneous | 30 min, 1 h, 6 h, 12 h, 24 h, and 1 week after the mercury administration |
| [127] |
In-vitro Human brain microvascular endothelial cells | (1, 2, 3, and 5 µM) MeHg | 24 h |
| [128] |
In- vitro Bovine aortic endothelial cells (BAECs) | 1 μM MeHg | 1, 3 or 6 h, 24 h |
| [129] |
In-vitro Human brain microvascular endothelial cells | 1, 2, 3 µM MeHg | 24 h |
| [119] |
In-vitro PC12 cells | 0, 10, 100, 1000 nM HgCl2 | 48 h |
| [130] |
System | Concentration | Exposure Duration | Toxicity | Ref. |
---|---|---|---|---|
Invitro HUVECs | 5 µM arsenic trioxide | 24 h |
| [164] |
In vitro SVEC4-10 | 7.5 µM arsenic trioxide | 4–6 h |
| [165] |
In vitro SVEC4-10 | 5 and 7.5 µM arsenic trioxide | 4–6 h |
| [166] |
In vitro HAEC | 1, 10, 100, and 1000 ng/mL Arsenic trioxide | 5–72 h |
| [167] |
In vitro HUVECs | 1–5 µM Sodium arsenite | 24 h |
| [168] |
Invivo Kunming mice | 0.15 mg 1.5 mg 15 mg arsenic trioxide/L Drinking water | whole lactation period (postnatal day 42) |
| [169] |
Invivo Wistar rats | 100 ppm Sodiumarsenite Drinking water | 60 days |
| [170] |
Invivo Wistar rats | 4–5 mg/kg/ day arsenite Drinking water | Gestation, lactation and until 4 months of age |
| [154] |
54 arsenicosis patients | - | - |
| [171] |
System | Concentration | ExposureDuration | Toxicity | Ref. |
---|---|---|---|---|
Zebrafish | 1 mg/L | 24 h and 96 h |
| [175] |
Zebrafish embryos | 9 µM 1.0 mg/L | 24 h 7 days |
| [176] [177] |
Mice | 3 mg/L Drinking water | 20 weeks |
| [192] |
Rats | 3 mg/kg Orally | 28 days |
| [193] |
Rats | 5 mg/kg bodyweight Orally | 21 days |
| [179] |
Rabbits | CdCl2 3 mg/kg × bw Orally | 30 days |
| [183] |
Rats | 32.5 ppm Drinking water | 2, 3- and 4-month |
| [184] |
Juvenile mice | 3.74 mg/kg Orally | 10 days |
| [185] |
Rats | 4 mg/kg bw i.p. Route | Single-dose |
| [189] |
Compound Name | Abbreviation | Molecular Formula | Structure |
---|---|---|---|
Calcium Disodium Ethylenediamine Tetra acetic Acid | CaNa2EDTA | C10H12CaN2Na2O8 | |
British Anti-Lewisite or 2,3- Dimercaprol | BAL | C3H8OS2 | |
Tetrathiomolybdate | TM | MoS42- | |
D-Pencillamine | DPA | C5H11NO2S | |
meso-2,3-dimercaptosuccinic acid | DMSA | C4H6O4S2 | |
Sodium 2,3 Dimercaptopropane-l-Sulphonate | DMPS | C3H7NaO3S3 | |
Monoisoamyldimercaptosuccinic acid | MiADMSA | C9H16O4S2 |
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Patwa, J.; Flora, S.J.S. Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies. Int. J. Mol. Sci. 2020, 21, 3862. https://doi.org/10.3390/ijms21113862
Patwa J, Flora SJS. Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies. International Journal of Molecular Sciences. 2020; 21(11):3862. https://doi.org/10.3390/ijms21113862
Chicago/Turabian StylePatwa, Jayant, and Swaran Jeet Singh Flora. 2020. "Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies" International Journal of Molecular Sciences 21, no. 11: 3862. https://doi.org/10.3390/ijms21113862
APA StylePatwa, J., & Flora, S. J. S. (2020). Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies. International Journal of Molecular Sciences, 21(11), 3862. https://doi.org/10.3390/ijms21113862