Emerging Role of Flavonoids as the Treatment of Depression
Abstract
:1. Introduction
2. Flavonoids and Structure Activity Relationship
2.1. Flavones
Structure Activity Relationship (SAR) of Flavones
- The presence of ketonic group at C4 and ring B, C may be responsible for enhancement of BDNF level in the brains of mice.
- Attachment of hydroxyl group at C7 and long chain group at C8 resulting in increment of activity of serotonin and nor-epinephrine pathways.
- Hydroxyl group at C3′ and C4′ is necessary for increments of anti-oxidant potential and radical scavenging properties.
- At C3′ and C4′ position, mono-substitution enhances the selectivity towards MAO-A inhibition, whereas di-substitution increases the selectivity for MAO-B inhibition.
- Glycoside-O linkage at C7 abolished or reduces the MAO inhibitory potential.
- Acetate and methyl group at C7 and C8 decreased antioxidant potential of flavones.
2.2. Flavonols
SAR of Flavonols
- In flavonols, attachment at C3 with –OR, does not much affect the antidepressant potential.
- Substitution at C3 with hydroxyl group resulting in increase of brain levels of neurotransmitter, i.e., serotonin, dopamine, nor-epinephrine.
- The presence of ketonic group at C4 and ring B, C may be necessary for anti-depressant potential of flavonols.
- Substitution at –OR at C3 with long chain molecules (C6H11O5 or C6H11O6) resulting in decrease activation of hypothalamic-pituitary-adrenal axis, thereby decrease the release of ACTH.
- Substitution of –OR at C3 with long chain molecule may be responsible for decrease in BDNF activity of flavonols.
- Substitution of –OR with –OH group decreases the MAO inhibitory potential.
- Hydroxyl group at C3′ and C4′ is necessary for increment of antioxidant potential and radical scavenging property.
- Acetate and methyl group at C7 and C8 decreased antioxidant potential of flavones.
- Glycoside-O linkage at C7 abolished or reduces the MAO inhibitory potential.
2.3. Flavanones
SAR of Flavanones
- In flavanones, there is absence of double bond at C2 and C3 position; it means this bond is not necessary for antidepressant potential.
- Saturation of double bond at C2 and C3 position does not much affect the BDNF activity of flavanones.
- Saturation of double bond at C2 and C3 position reduces the MAO inhibitory potential.
- Substitution at C7 with O- (C12H21O9) may be responsible for selective interaction with kappa-opioid receptors.
- Glycoside-O linkage at C7 abolished or reduces the MAO inhibitory potential.
- Acetate and methyl group at C7 and C8 decreased antioxidant potential of flavonols.
- Hydroxyl group at C3′ and C4′ is necessary for an increment of antioxidant potential and radical scavenging property.
- Hydroxyl group at C3′ may be responsible for reduction in acetyl-cholinesterase activity.
2.4. Flavanonols
2.5. Flavanols
2.6. Others
3. Possible Cellular and Molecular Mechanism of Anti-Depressant Action of Flavonoids
3.1. Flavonoids and Neurotransmitters
3.2. Flavonoids and Neurodegeneration
3.3. Flavonoids and Oxidative Stress
3.4. Flavonoids and BDNF Expression
4. Future Aspects
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
5-HT | 5-Hydroxy tryptophan |
MDD | Major depression disorder |
MAO | Monoamino oxidase |
D1 | Dopamine 1 |
D2 | Dopamine 2 |
COX | Cyclooxygenase |
XO | Xanthine oxidase |
NOS | Nitric oxide synthase |
LOX | Lipooxygenase |
IP3 | Inositol triphosphate |
PKC | Phosphokinase C |
BDNF | Brain derived neurotrophic factor |
CREB | cAMP-response element binding protein |
NO | Nitric oxidase |
SOD | Superoxide dismutase |
BCL-2 | B-cell lymphoma 2 |
TrkB | Tropomyosin receptor kinase B |
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Sr. No. | Flavones | C5 | C6 | C7 | C8 | C3′ | C4′ |
---|---|---|---|---|---|---|---|
1. | 7,8-Dihydroxyflavone | -OH | -OH | ||||
2. | Amentoflavone | -OH | -OH | -C15H12O5 | -OH | ||
3. | Apigenin | -OH | -OH | -OH | |||
4. | Baicalein | -OH | -OH | -OH | |||
5. | Chrysin | -OH | -OH | ||||
6. | Luteolin | -OH | -OH | -OH | -OH | ||
7. | Nobiletin | -OCH3 | -OCH3 | -OCH3 | -OCH3 | -OCH3 | |
8. | Orientin | -OH | -OH | -C6H11O5 | -OH | -OH | |
9. | Vitexin | -OH | -OH | -C6H11O5 | -OH |
Sr. No. | Flavonols | R | C5 | C6 | C7 | C8 | C3′ | C4′ | C5′ |
---|---|---|---|---|---|---|---|---|---|
1. | 3,5,6,7,8,3′,4′-Heptamethoxyflavone | -CH3 | -OCH3 | -OCH3 | -OCH3 | -OCH3 | -OCH3 | -OCH3 | |
2. | Fisetin | H | OH | OH | OH | ||||
3. | Hyperoside | (C6H11O5) | -OH | -OH | -OH | -OH | |||
4. | Icariin | H | OH | -O(C6H11O5) | C5H9 | OCH3 | |||
5. | Isoquercitrin | -(C6H11O5) | OH | OH | OH | OH | |||
6. | Kaempferitrin | (C6H11O4) | -OH | -O(C6H11O4) | -OH | ||||
7. | Kaempferol | H | OH | OH | OH | ||||
8. | Kaempferol-3-O-β-D-glucose | -(C6H11O5) | OH | OH | OH | ||||
9. | Miquelianin | -(C6H9O6) | OH | OH | OH | OH | |||
10. | Myricetin | H | OH | OH | OH | OH | OH | ||
11. | Myricitrin | -(C6H11O4) | OH | OH | OH | OH | OH | ||
12. | Quercetin | H | OH | OH | OH | OH | |||
13. | Quercetin-3-O-β-D-glucose | -(C6H11O5) | OH | OH | OH | OH | |||
14. | Quercitrin | -(C6H11O4) | OH | OH | OH | OH | |||
15. | Rutin | -(C12H21O9) | OH | OH | OH | OH |
Sr. No. | Flavanone | C5 | C7 | C3′ | C4′ |
---|---|---|---|---|---|
1. | Hesperidin | -OH | -O(C12H21O9) | -OH | -OCH3 |
2. | Isosakuranetin-5-O-rutinoside | -O(C12H21O9) | -OH | -OCH3 | |
3. | Liquiritin | -OH | -O(C6H11O5) | ||
4. | Naringenin | -OH | -OH | -OH | |
5. | Naringin | -OH | -O(C12H20O9) |
Sr. No. | Flavanonols | R’ | C5 | C6 | C3′ | C4′ | C5′ |
---|---|---|---|---|---|---|---|
1. | Astilbin | -O(C6H11O4) | -OH | -OH | -OH | -OH | |
2. | Dihydromyricetin | -H | -OH | -OH | -OH | -OH | -OH |
Flavones | ||||||
---|---|---|---|---|---|---|
Isolated Bioactive Flavonoids | Doses | Route | Animal Species | Treatment Duration | Mechanism of Actions | References |
7,8-Dihydroxyflavone | 1, 3, and 10 mg/kg | Intra-gastric | Male Swiss mice | 60 min before test |
| [41] |
10 and 20 mg/kg | Intraperitoneal | Male C57BL/6 mice | 28 days |
| [42] | |
5 mg/kg | Oral | Male C57BL/6 mice | 21 days |
| [43] | |
Amentoflavone | 6.25, 12.5, 25, or 50 mg/kg | Oral | Male Swiss albino mice | 3 days |
| [45] |
Apigenin | 12.5 and 25 mg/kg | I.p. | Male ddY mice | 1 h |
| [47] |
20 mg/kg | I.g. | Male Sprague–Dawley rats | 21 days |
| [48] | |
20 and 40mg/kg | Oral | Male ICR mice | 21 days |
| [49] | |
25, 50 mg/kg | I.p. | Male ICR mice | 7 days |
| [51] | |
Baicalein | 1, 2, or 4 mg/kg | I.p. | Male Kunming mice | 7 and 21 days |
| [54] |
10, 20, and 40 mg/kg | I.p. | Male Sprague–Dawley rats | 14 days |
| [55] | |
10, 20, or 40 mg/kg | Oral | Male Wistar rats | 35 days |
| [56] | |
Chrysin | 5 and 20 mg/kg | Oral | Female C57B/6J mice | 28 days |
| [60] |
5 and 20 mg/kg | Oral | Male C57B/6J mice | 14 days |
| [61] | |
5 and 20 mg/kg | Oral | Female C57B/6J mice | 28 days |
| [62] | |
Luteolin | 50 mg/kg | Oral | Male ICR mice | 23 days |
| [63] |
5 or 10 mg/kg | Oral | Male ICR mice | 30 min before test |
| [64] | |
Nobiletin | 20, 50, or 100 mg/kg | Oral | Male ICR mice | After 60 min |
| [66] |
Orientin | 20 and 40 mg/kg | Oral | Male Kunming mice | 21 days |
| [68] |
Vitexin | 10,20 and 30 mg/kg | Oral | Male BALB/c mice | 60 min before test |
| [77] |
Flavonols | ||||||
3,5,6,7,8,3′,4′-Heptamethoxyflavone | 50 mg/kg | S.c. | C57BL/6 mice | 25 days |
| [80] |
Fisetin | 10 or 20 mg/kg | Oral | Male ICR mice | 4 days |
| [83] |
20, 40, or 80 mg/kg | Oral | Male ICR mice | 7 days |
| [84] | |
5 mg/kg | Oral | Male ICR mice | 21 days |
| [85] | |
Hyperoside | 2.5, 5, and 10 μg/mL | I.p. | PC12 cell line | 4 h |
| [87] |
10, 20, or 40 mg/kg | I.p. | Male CF1 mice | 14 days |
| [88] | |
0.6 mg/kg | Oral | Male CD rats | 14–56 days |
| [89] | |
Icariin | 20 and 40 mg/kg | Oral | Male Sprague–Dawley rats | 35days |
| [91] |
5 and 10 mg/kg | Oral | Male C57BL/6J mice | 28 days |
| [92] | |
20 and 40 mg/kg | Oral | Male Sprague–Dawley rats | 35 days |
| [93] | |
60 mg/kg | Oral | Male Sprague–Dawley rats | 21 days |
| [94] | |
Isoquercitrin | 0.6 mg/kg | Oral | Male CD rats | 14–56 days |
| [89] |
2.5 mg/kg | Oral | Male Sprague–Dawley rats | 14 days |
| [95] | |
Kaempferitrin | 1, 5, 10, or 20 mg/kg | Oral | Male Swiss Webster mice | 4 days |
| [98] |
Kaempferol | 30 mg/kg/day | Oral | Male ICR mice | 14 days |
| [100] |
0.35 mM/kg | I.p. | Male Swiss mice | 60 min prior to the test |
| [101] | |
Kaempferol-3-O-β-D-glucose | 0.35 mM/kg | I.p. | Male Swiss mice | 60 min prior to the test |
| [101] |
Miquelianin | 0.6 mg/kg | Oral | Male CD rats | 14 days |
| [89] |
Myricetin | 50 mg/kg | I.p. | Male C57BL/6 mice | 21 days |
| [104] |
Myricitrin | 10 mg/kg | I.p. | Male Balb/C mice | 21 days |
| [106] |
Quercetin | 2.5, 5, 10, 20 and 40 mg/kg | Oral | Male Sprague–Dawley rats | 14 days |
| [95] |
0.35 mM/kg | I.p. | Male Swiss mice | 60 min prior to the test |
| [101] | |
50 or 100 mg/kg | I.p. | Male Wistar rats | 21 days |
| [108] | |
40 and 80 mg/Kg | Oral | Male olfactory bulbectomy rats | 14 days |
| [109] | |
25 mg/kg | Oral | Female Swiss mice | 14 days |
| [211] | |
Quercetin- 3-O-β-D-glucose | 0.35 mM/kg | I.p. | Male Swiss mice | 60 min prior to the test |
| [101] |
Quercitrin | 30 mg/kg/day | Oral | Male ICR mice | 14 days |
| [100] |
Rutin | 0.3, 1, 3, 10 mg/kg | Oral | Male Swiss mice | 4 days |
| [8] |
5 and 10 mg/kg | Oral | Male Sprague–Dawley rats | 14 days |
| [95] | |
Flavanones | ||||||
Hesperidin | 25, 50, or 100 mg/kg | Oral | Male albino Wistar rats | 21 days |
| [117] |
0.01, 0.1, 0.3, and 1 mg/kg | I.p | Male Swiss mice | 21 days |
| [118] | |
0.01, 0.1, 0.3, and 1 mg/kg | I.p. | Male Swiss mice | 21 days |
| [119] | |
25 and 50 mg/kg | Oral | Male ICR mice | 21 days |
| [121] | |
0.01, 0.1, 0.3, and 1 mg/kg | I.p. | Male Swiss mice | 21 days |
| [122] | |
0.4, 4, 8, 16, and 32 mg/kg | Oral | Male imprinting control region mice | After 1 h |
| [119] | |
50 mg/kg | Oral | Male C57BL/6 mice | 13 days |
| [217] | |
Isosakuranetin-5-O-rutinoside | 15 and 30 mg/kg | Oral | Male ICR mice | 24, 18, and 1 h before test |
| [123] |
Liquiritin | 10, 20 and 40 mg/kg | G.i. | Male mice | 30 min before Sample |
| [124] |
Isoliquiritin | 10, 20 and 40 mg/kg | G.i. | Male mice | 30 min before sample |
| [124] |
Naringenin | 5, 10 and 20 mg/kg | Oral | Male ICR mice | 14 days |
| [130] |
20 mg/kg | Oral | Male ICR mice | 21 days |
| [128] | |
Naringin | 50 and 100 mg/kg | I.p. | Male Wistar rats | 14 days |
| [133] |
Flavanonols | ||||||
Astilbin | 10, 20, or 40 mg/kg | I.p. | Male C57BL/6J mice | 21 days |
| [136] |
Dihydromyricetin | 10 and 20 mg/kg | I.p. | Male C57BL/6J mice | 7 days |
| [137] |
Flavanols | ||||||
Catechin | 88.6 and 58.9 µM | - | Wistar male rat | - |
| [139] |
Epicatechin | 88.6 and 58.9 µM | - | Wistar male rat | - |
| [139] |
Epigallocatechin gallate | 500 ng/mL | - | Sprague–Dawley rat brains | 24 h |
| [141] |
Other flavonoids | ||||||
Silibinin | 100 and 200 mg/kg | Oral | Either sex Wistar rats | 14 days |
| [143,144] |
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Pannu, A.; Sharma, P.C.; Thakur, V.K.; Goyal, R.K. Emerging Role of Flavonoids as the Treatment of Depression. Biomolecules 2021, 11, 1825. https://doi.org/10.3390/biom11121825
Pannu A, Sharma PC, Thakur VK, Goyal RK. Emerging Role of Flavonoids as the Treatment of Depression. Biomolecules. 2021; 11(12):1825. https://doi.org/10.3390/biom11121825
Chicago/Turabian StylePannu, Arzoo, Prabodh Chander Sharma, Vijay Kumar Thakur, and Ramesh K. Goyal. 2021. "Emerging Role of Flavonoids as the Treatment of Depression" Biomolecules 11, no. 12: 1825. https://doi.org/10.3390/biom11121825
APA StylePannu, A., Sharma, P. C., Thakur, V. K., & Goyal, R. K. (2021). Emerging Role of Flavonoids as the Treatment of Depression. Biomolecules, 11(12), 1825. https://doi.org/10.3390/biom11121825