Depressive disorders are among the most disabling diseases experienced around the world. The search for new pharmacological alternatives to treat depression is a global priority. In preclinical research, molecules obtained from plants, such as flavonoids, have shown promising antidepressant-like properties through several mechanisms of action that have not been fully elucidated, including crossing of the blood brain barrier (BBB).
Flavonoid | Experimental Subjects | Treatment | Behavioral Effect | Effect on Serotonergic System | Reference | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Astilbin (taxifolin-3-O-rhamnoside) |
Adult male C57BL/6J mice | 10, 20, and 40 mg/kg (i.p.) for 21 days | ↓ TTI in FST and TST ↑ Sucrose intake |
↑ 5-HT in frontal cortex | [32][168] | ||||||
Hesperidin (3,5,7-trihydroxyflavanone-7-rhamnoglucoside) |
Male adult Swiss mice | 0.1, 0.3, and 1 mg/kg (i.p.) S.D. 30 min before behavioral test | ↓ TTI in FST and TST | Pretreatment with pCPA (100 mg/kg, i.p.) prevents antidepressant-like effect | [33][169] | ||||||
Adult male Wistar rats with hyperglycemia induced by streptozotocin | 25, 50, and 100 mg/kg (p.o.) for 21 days | ↓ TTI in FST | ↑ Brain levels of 5-HT | [34][170] | |||||||
Male Swiss Albino mice | 1 mg/kg (i.p.) for 14 days | ↓ TTI in FST and TST | ↑ 5-HT in HP and cerebral cortex | [35][171] | |||||||
Old male Sprague-Dawley rats | 20, 50, and 100 mg/kg (i.p.) for 14 days | ↑ Sucrose intake ↓ TTI in FST |
↑ 5-HT in HP, PFC, and amygdala | [36][172] | |||||||
Rutin (quercetin-3-O-rhamnosylglucoside) |
Male Swiss mice | 0.01, 0.1, 0.3, 1, 3, and 10 mg/kg (p.o.) 60 min before the behavioral test | ↓ TTI in FST | Pretreatment with pCPA (100 mg/kg, i.p.) prevents antidepressant-like effect | [37][173] | ||||||
Five weeks old male Sprague Dawley rats | 225 mg/kg (p.o.) for 28 days | ↓ TTI ↑ Swimming time in FST |
↑ 5-HT in frontal cortex, HP, striatum, and amygdala | [38][174] | |||||||
Icariin (7-(β-D-Glucopyranosyloxy)-5-hydroxy-4′-methoxy-8-(3-methylbut-2-en-1-yl)-3-(α-L-rhamnopyranosyloxy) flavone) |
Adult male Wistar rats | 30 and 60 mg/kg (p.o.) for 5 weeks | ↑ Sucrose intake | ↑ 5-HT1A mRNA levels in HP and frontal cortex | [39][175] | ||||||
Orientin (luteolin-8-C-glucoside) |
Adult male Kunming mice | 20 and 40 mg/kg (p.o.) 3 weeks | ↑ Sucrose intake | ↑ 5-HT in HP and PFC |
[40] | ||||||
Hyperoside (quercetin 3-galactoside) |
Male Albino Swiss mice | 3.75 mg/kg (i.p.) 60 min before the behavioral test | ↓ TTI in FST and TST | Pretreatment with pCPA (100 mg/kg, i.p.) prevented antidepressant-like effect of hyperoside | [41][176] | ||||||
Quercetin | Male Swiss Albino mice | 25 mg/kg (p.o.) for 4 weeks | ↓ TTI in FST and TST | ↑ Brain levels of 5-HT | [10][100] | ||||||
Fisetin | Male ICR mice | 10 and 20 mg/kg (p.o.) 60 min before behavioral test | ↓ TTI in FST and TST | ↑ 5-HT in frontal cortex and HP | [30][166] | ||||||
Vixetin (apigenin-8-C-glucopyranoside) |
Adult male BALB/c mice | 10, 20, and 30 mg/kg (p.o.) 60 min before behavioral test | ↓ TTI in FST and TST | Pretreatment with NAN 190, a 5-HT1A antagonist (0.5 mg/kg, i.p.) prevented antidepressant-like effect of vixetin | [42][177] | ||||||
[ | 42 | ] | [ | 177 | ] | Apigenin | Male ICR mice | 7, 10, 14, and 20 mg/kg (p.o.) for 2 weeks | ↓ TTI in FST ↑ Sucrose intake |
↑ 5-HT in PFC, HP, hypothalamus and nucleus accumbens of rats exposed to CMS | [43][178] |
Apigenin | Male ICR mice | 7, 10, 14, and 20 mg/kg (p.o.) for 2 weeks | ↓ TTI in FST ↑ Sucrose intake |
↑ 5-HT in PFC, HP, hypothalamus and nucleus accumbens of rats exposed to CMS | [43][178] | Albino mice (either sex) | 25 and 50 mg/kg (p.o.) 24, 5, and 1 h before the behavioral test | ||||
Albino mice (either sex) | 25 and 50 mg/kg (p.o.) 24, 5, and 1 h before the behavioral test | ↓ TTI in TST and FST | Pretreatment with pCPA (100 mg/kg, i.p.) prevented antidepressant-like effect of apigenin | [44][179] | |||||||
↓ TTI in TST and FST | Pretreatment with pCPA (100 mg/kg, i.p.) prevented antidepressant-like effect of apigenin | [ | 44 | ][179] | Naringenin (4′,5,7-trihydroxyflavanone-7-rhamnoglucoside) |
Male ICR mice | 10, 20, and 50 mg/kg (p.o.) 60 min before the behavioral test | ↓ TTI in TST | Pretreatment with pCPA (100 mg/kg, i.p.) prevented antidepressant-like effect of naringenin | [45][180] | |
Three months old BALB/c male mice | 25, 50, and 100 mg/kg (p.o.) for 14 days | ↑ Sucrose intake | |||||||||
Naringenin (4′,5,7-trihydroxyflavanone-7-rhamnoglucoside) |
Male ICR mice | 10, 20, and 50 mg/kg (p.o.) 60 min before the behavioral test | ↓ TTI in TST | Pretreatment with pCPA (100 mg/kg, i.p.) prevented antidepressant-like effect of naringenin | [45][180] | ↓ TTI in FST | ↑ 5-HT in cortex and HP | [ | |||
Three months old BALB/c male mice | 25, 50, and 100 mg/kg (p.o.) for 14 days | 46 | ] | [181] | |||||||
↑ Sucrose intake | ↓ TTI in FST | ↑ 5-HT in cortex and HP | [46][181] | Silibinin | 6–8 weeks old Kunming mice | 100, 200, and 400 mg/kg (p.o.) for 3 weeks | ↓ TTI in TST and FST | ↑ 5-HT in PFC and HP | [47 | ||
Silibinin | 6–8 weeks old Kunming mice | ] | [ | 182 | ] | ||||||
100, 200, and 400 mg/kg (p.o.) for 3 weeks | ↓ TTI in TST and FST | ↑ 5-HT in PFC and HP | [ | 47 | ][182] | Eight weeks old male Sprague Dawley rats | 25, 50, and 100 mg/kg (i.p.) for 14 days | ↓ TTI in the FST ↑ Sucrose intake |
|||
Eight weeks old male Sprague Dawley rats | 25, 50, and 100 mg/kg (i.p.) for 14 days | ↑ 5-HT in HP and amygdala, and enhanced expression of TpH-1 mRNA in HP | [ | ↓ TTI in the FST 48][183] |
|||||||
↑ Sucrose intake | ↑ 5-HT in HP and amygdala, and enhanced expression of TpH-1 mRNA in HP | [ | 48 | ][183] | Chrysin | Male C57B/6J mice | 5 and 20 mg/kg (p.o.) for 14 days | ↓ TTI in FST | ↑ 5-HT in HP | [29][130] | |
Chrysin | Male C57B/6J mice | 5 and 20 mg/kg (p.o.) for 14 days | ↓ TTI in FST | Adult female C57BL/6 mice | 20 mg/kg (p.o.) for 28 days | ↓ TTI in FST and TST | ↑ 5-HT in PFC and HP | [49][184] | |||
Male Wistar rats | 5 mg/kg (p.o.) for 28 days | ↓ TTI in FST | ↓ 5-HT1A and 5-HT2A mRNA in raphe nucleus ↑ 5-HT1A mRNA in HP |
[50][185] | |||||||
Nobiletin | Male ICR mice | 25, 50, and 100 mg/kg (p.o.) 60 min before the behavioral test | ↓ TTI in FST and TST | Pretreatment with WAY 100,635 (7.1 mg/kg, s.c., a serotonin 5-HT1A receptor antagonist) and cyproheptadine (3 mg/kg, i.p., a serotonin 5-HT2 receptor antagonist) prevented antidepressant-like effect of Nobiletin |
[51][186] | ||||||
Liquiritin (7-Hydroxyflavanone 4′-O-glucoside) and Isoliquiritin (2′,4,4′-Trihydroxychalcone 4-glucoside) |
Mice | 10, 20, and 40 mg/kg (p.o.) 30 min before the behavioral test | ↓ TTI in FST and TST | ↑ 5-HT in HP, hypothalamus and cortex |
[52][187] |
Flavonoid | Experimental Subjects | Treatment | Behavioral Effect | Effect on Serotonergic System | Reference |
---|---|---|---|---|---|
Astilbin (taxifolin-3-O-rhamnoside) |
Adult male C57BL/6J mice | 10, 20, and 40 mg/kg (i.p.) for 21 days | ↓ TTI in FST and TST ↑ Sucrose intake |
↑ 5-HT in frontal cortex | [32][168] |
Hesperidin (3,5,7-trihydroxyflavanone-7-rhamnoglucoside) |
Male adult Swiss mice | 0.1, 0.3, and 1 mg/kg (i.p.) S.D. 30 min before behavioral test | ↓ TTI in FST and TST | Pretreatment with pCPA (100 mg/kg, i.p.) prevents antidepressant-like effect | [33][169] |
Adult male Wistar rats with hyperglycemia induced by streptozotocin | 25, 50, and 100 mg/kg (p.o.) for 21 days | ↓ TTI in FST | ↑ Brain levels of 5-HT | [34][170] | |
Male Swiss Albino mice | 1 mg/kg (i.p.) for 14 days | ↓ TTI in FST and TST | ↑ 5-HT in HP and cerebral cortex | [35][171] | |
Old male Sprague-Dawley rats | 20, 50, and 100 mg/kg (i.p.) for 14 days | ↑ Sucrose intake ↓ TTI in FST |
↑ 5-HT in HP, PFC, and amygdala | [36][172] | |
Rutin (quercetin-3-O-rhamnosylglucoside) |
Male Swiss mice | 0.01, 0.1, 0.3, 1, 3, and 10 mg/kg (p.o.) 60 min before the behavioral test | ↓ TTI in FST | Pretreatment with pCPA (100 mg/kg, i.p.) prevents antidepressant-like effect | [37][173] |
Five weeks old male Sprague Dawley rats | 225 mg/kg (p.o.) for 28 days | ↓ TTI ↑ Swimming time in FST |
↑ 5-HT in frontal cortex, HP, striatum, and amygdala | [38][174] | |
Icariin (7-(β-D-Glucopyranosyloxy)-5-hydroxy-4′-methoxy-8-(3-methylbut-2-en-1-yl)-3-(α-L-rhamnopyranosyloxy) flavone) |
Adult male Wistar rats | 30 and 60 mg/kg (p.o.) for 5 weeks | ↑ Sucrose intake | ↑ 5-HT1A mRNA levels in HP and frontal cortex | [39][175] |
Orientin (luteolin-8-C-glucoside) |
Adult male Kunming mice | 20 and 40 mg/kg (p.o.) 3 weeks | ↑ Sucrose intake | ↑ 5-HT in HP and PFC |
[40] |
Hyperoside (quercetin 3-galactoside) |
Male Albino Swiss mice | 3.75 mg/kg (i.p.) 60 min before the behavioral test | ↓ TTI in FST and TST | Pretreatment with pCPA (100 mg/kg, i.p.) prevented antidepressant-like effect of hyperoside | [41][176] |
Quercetin | Male Swiss Albino mice | 25 mg/kg (p.o.) for 4 weeks | ↓ TTI in FST and TST | ↑ Brain levels of 5-HT | [10][100] |
Fisetin | Male ICR mice | 10 and 20 mg/kg (p.o.) 60 min before behavioral test | ↓ TTI in FST and TST | ↑ 5-HT in frontal cortex and HP | [30][166] |
Vixetin (apigenin-8-C-glucopyranoside) |
Adult male BALB/c mice | 10, 20, and 30 mg/kg (p.o.) 60 min before behavioral test | ↓ TTI in FST and TST | Pretreatment with NAN 190, a 5-HT1A antagonist (0.5 mg/kg, i.p.) prevented antidepressant-like effect of vixetin | |
↑ 5-HT in HP | |||||
[ | |||||
29 | |||||
] | |||||
[ | |||||
130 | ] | ||||
Adult female C57BL/6 mice | 20 mg/kg (p.o.) for 28 days | ↓ TTI in FST and TST | ↑ 5-HT in PFC and HP | [49][184] | |
Male Wistar rats | 5 mg/kg (p.o.) for 28 days | ↓ TTI in FST | ↓ 5-HT1A and 5-HT2A mRNA in raphe nucleus ↑ 5-HT1A mRNA in HP |
[50][185] | |
Nobiletin | Male ICR mice | 25, 50, and 100 mg/kg (p.o.) 60 min before the behavioral test | ↓ TTI in FST and TST | Pretreatment with WAY 100,635 (7.1 mg/kg, s.c., a serotonin 5-HT1A receptor antagonist) and cyproheptadine (3 mg/kg, i.p., a serotonin 5-HT2 receptor antagonist) prevented antidepressant-like effect of Nobiletin |
[51][186] |
Liquiritin (7-Hydroxyflavanone 4′-O-glucoside) and Isoliquiritin (2′,4,4′-Trihydroxychalcone 4-glucoside) |
Mice | 10, 20, and 40 mg/kg (p.o.) 30 min before the behavioral test | ↓ TTI in FST and TST | ↑ 5-HT in HP, hypothalamus and cortex |
[52][187] |