Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development
Abstract
:1. Introduction
2. Pre-Clinical Evidence of Flavonoids for Pain Control
2.1. Flavonols
2.2. Flavones
2.3. Flavanones
2.4. Chalcone
2.5. Flavanols, Flavan-3-ols or Catechins
3. Structure-Activity Relationship (SAR)
4. Clinical Studies and Safety
4.1. Hesperidin
4.2. Catechins
4.3. Quercetin
4.4. Apigenin
4.5. Flavonoid-Based Compounds
5. Development of Pharmaceutical Formulations Containing Flavonoids
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Flavonoids Groups | Flavonoid | Cell Line | Effects | Refs | |
---|---|---|---|---|---|
Flavonols | Quercetin | macrophages | RAW 264.7 | Reduce TNF-α, IL-1β and IL-6 production | [75] |
BMDM | Inhibit ASC speck formation and ASC oligomerization | [57] | |||
BMDM | Modulate M1 and M2 | [85] | |||
RAW 264.7 | [83] | ||||
J 774 | [84] | ||||
neutrophils | Human neutrophils | Modulate actin polymerization | [76] | ||
dendritic cell | BMDC | Activation and Maturation | [81,82] | ||
mast cells | HMC-1 | Reduce TNF-α, IL-1β, IL-8 and IL-6 production | [77] | ||
hCBMCs | Reduce histamine, leukotrienes and PGD2 | [78] | |||
monocytes | Human THP-1 monocytic cells THP-1 | Reduce TNF-α, and IL-1β production | [79,80] | ||
Rutin | macrophages | RAW 264.7 | promote M2 polarization | [95] | |
CD11b+ primary macrophages | |||||
neutrophils | Human peripheral blood neutrophils | Reduce NO and TNF-α production | [96] | ||
mast cells | HMC-1 | Reduce TNF-α, IL-1β, IL-8 and IL-6 production | [77] | ||
monocytes | Human THP-1 | Inhibit adhesion | [97] | ||
Flavones | Apigenin | macrophages | ANA-1 | Modulate macrophages polarization | [102] |
RAW264.7 | |||||
RAW 264.7 | Reduce NO production and COX-2 expression | [105] | |||
neutrophils | Human peripheral blood neutrophils | Down-regulation of Mcl-1 | [103] | ||
dendritic cell | BMDC | Inhibit maturation and migration | [35,104] | ||
mast cells | HMC-1 | Inhibit TNF-α, IL-8, IL-6, GM-CSF, and COX-2 expression and NF-kB activation | [106] | ||
monocytes | monocytes to HUVEC | Reduce TNF-α, production | [105] | ||
Vitexin | macrophages | RAW 264.7 | Inhibit TNF-α, IL-1β, NO, PGE2 and increase in IL-10 release | [113] | |
neutrophils | Human peripheral blood neutrophils | Reduce NO, TNF-α, and MPO production | [112] | ||
mast cells | RBL-2H3 | Prevent degranulation | [111] | ||
Diosmin | macrophages | RAW264.7 | Reduce NO, PGE2, IL-6, IL-12, TNF-α production | [120] | |
Flavanones | Naringenin | macrophages | U937 | Regulate activation | [129] |
neutrophils | Human peripheral blood neutrophils | Regulate microbicidal activity | [130] | ||
dendritic cell | BMDC | Reduce maturation | [131] | ||
Hesperidin | macrophages | RAW264.7 | Modulate M1 polarization | [70] | |
neutrophils | Human peripheral blood neutrophils | Reduce generate superoxide radical | [140] | ||
mast cells | HMC-1 | Reduce TNF-α and IL-1β production | [141] | ||
Chalcone | Trans-chalcone | macrophages | BMDM | Reduce IL-1β production | [42] |
Hesperidin methyl chalcone | macrophages | RAW264.7 | Reduce IL-33, TNF-α, and IL-6 levels | [141] | |
Flavan-3-ols | Epigallocatechin-3-gallate | macrophages | RAW 264.7 | Reduce NO, prostaglandin PGE2 and COX-2 production | [147] |
neutrophils | Murine peritoneal neutrophils | Reduce chemotaxis | [150] | ||
dendritic cell | Human dendritic cell | Differentiation and maturation | [148] | ||
mast cells | RBL-2H3 | Inhibit degranulation | [149] |
Flavonoid/Flavonoid-Based Compound | n | Treatment | Duration | Outcomes | Refs |
---|---|---|---|---|---|
Flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, and polymers | 49,281 men in the HPFS and 80,336 women from the NSH | Food frequency questionnaire | 20–22 years of follow-up | Intake of some flavonoids may reduce Parkinson disease risk, particularly in men | [193] |
Hesperidin | 24 | 500 mg, daily | 3 weeks | Increased flow-mediated dilation and reduced concentrations of circulating inflammatory biomarkers | [195] |
100 | Daflon 500 mg (3 tablets bid. the first 4 days and 2 tablets bid. the following 3 days) | 7 days | Clinical severity, inflammation, congestion, edema, prolapse, duration, and severity of hemorrhoidal episode diminished | [196] | |
120 | Daflon 500 mg, 2 tablets, daily | 2 months | The overall symptom score decreased when compared to placebo | [197] | |
105 | Daflon 500 mg, 2 tablets, daily | 4 weeks + follow-up for 6 months | Improvement in pain, heaviness, bleeding, pruritus, and mucosal discharge from baseline | [198] | |
56 | 379 mg of green tea extract | 3 months | Improvements in blood pressure, insulin resistance, inflammation and oxidative stress, and lipid profile in patients with obesity-related hypertension | [199] | |
Quercetin | 50 | 500 mg, daily | 8 weeks | Improvements in clinical symptoms, disease activity, hs-TNFα, and health assessment questionnaire in women with RA | [200] |
Apigenin | 100 | 2 mL of an oleogel preparation of reformulated traditional chamomile oil | Topical application, once | Pain, nausea, vomiting, photophobia, and phonophobia significantly decreased in patients with migraine without aura | [201] |
Silymarin (Livergol®, Goldaruo pharmaceutical, Iran) | 44 | 420 mg, daily | 90 days | Joint swelling, tenderness, and pain were reduced | [202] |
Pycnogenol® (Horphag Research Ltd., UK, Geneve, Switzerland) | 67 | 220 mg, daily | 3 weeks | Patients with OA decreased C reactive protein levels and reduced use of painkillers and non-steroidal anti-inflammatory drugs | [203] |
100 | 150 mg/day | 3 months | Patients with OA presented relief from daily pain, stiffness, and physical function | [204] | |
37 | 150 mg/day | 3 months | Alleviating OA symptoms and reducing the need for NSAIDs or COX-2 inhibitors administration | [205] | |
Alvocidib or Flavopiridol (Tolero Pharmaceuticals, Inc.) | 10 | 30-min loading dose of 30 mg/m (2) followed by a 4-h infusion of 30 mg/m (2) once weekly | 3 weeks every 5 weeks, twice | Reduction in tumor burden on chronic lymphocytic leukemia patients | [206] |
Formulations Containing Flavonoids | Flavonoids | Biological Effects |
---|---|---|
Microparticles | Quercetin [69] Rutin [266] | ↑ bioavailability ↑ absorption ↑ solubility ↑ stability ↑ efficacy |
Nanoparticles | Quercetin [267] Naringenin [268] Fisetin [269] | |
SNEDDS | Naringenin [270] Quercetin [271] Rutin [272,273] | |
Liposomal | Quercetin [274,275] Rutin [274] Kaempferol [275] Luteolin [275] | |
Inclusion Complex | Quercetin [276] Rutin [277] Naringenin [278] | |
Micelles | Quercetin [279] Rutin [280] | |
Solid Dispersion | Naringenin [281] |
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Ferraz, C.R.; Carvalho, T.T.; Manchope, M.F.; Artero, N.A.; Rasquel-Oliveira, F.S.; Fattori, V.; Casagrande, R.; Verri, W.A., Jr. Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development. Molecules 2020, 25, 762. https://doi.org/10.3390/molecules25030762
Ferraz CR, Carvalho TT, Manchope MF, Artero NA, Rasquel-Oliveira FS, Fattori V, Casagrande R, Verri WA Jr. Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development. Molecules. 2020; 25(3):762. https://doi.org/10.3390/molecules25030762
Chicago/Turabian StyleFerraz, Camila R., Thacyana T. Carvalho, Marília F. Manchope, Nayara A. Artero, Fernanda S. Rasquel-Oliveira, Victor Fattori, Rubia Casagrande, and Waldiceu A. Verri, Jr. 2020. "Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development" Molecules 25, no. 3: 762. https://doi.org/10.3390/molecules25030762