Review Article Advances in the Preclinical Study of Some Flavonoids As Potential Antidepressant Agents

Hindawi Scientiﬁca Volume 2018, Article ID 2963565, 14 pages https://doi.org/10.1155/2018/2963565

Review Article Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents

León Jesús German-Ponciano,1 Gilberto Uriel Rosas-Sánchez,1 Eduardo Rivadeneyra-Domínguez,2 and Juan Francisco Rodríguez-Landa 2,3

1 Programa de Doctorado en Neuroetolog´ıa, Instituto de Neuroetolog´ıa, Universidad Veracruzana, Xalapa, VER, Mexico 2Facultad de Qu´ımica Farmaceutica´ Biologica,´ Universidad Veracruzana, Xalapa, VER, Mexico 3Laboratorio de Neurofarmacolog´ıa, Instituto de Neuroetolog´ıa, Universidad Veracruzana, Xalapa, VER, Mexico

Correspondence should be addressed to Juan Francisco Rodr´ıguez-Landa; [email protected]

Received 25 August 2017; Revised 11 December 2017; Accepted 24 December 2017; Published 1 February 2018

Academic Editor: Marie-Aleth Lacaille-Dubois

Copyright © 2018 Leon´ Jesus´ German-Ponciano et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Flavonoids are phenolic compounds found commonly in plants that protect them against the negative efects of environmental insults. Tese secondary metabolites have been widely studied in preclinical research because of their biological efects, particularly as antioxidant agents. Diverse favonoids have been studied to explore their potential therapeutic efects in the treatment of disorders of the central nervous system, including anxiety and depression. Te present review discusses advances in the study of some favonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical efects and the apparent mechanism of action of their preclinical antidepressant-like efects. Natural favonoids produce antidepressant-like efects in validated behavioral models of depression. Te mechanism of action of these efects includes the activation of serotonergic, dopaminergic, noradrenergic, and �-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant efects of some natural favonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans.

1. Introduction inhibitors (e.g., fluoxetine and fuvoxamine), selective dopamine reuptake inhibitors (e.g., amineptine and methylpheni- Depression is one of the most frequently diagnosed psy- date), selective norepinephrine reuptake inhibitors (e.g., chiatric disorders in the general population, the symptoms reboxetine and viloxazine), and dual antidepressant drugs ofwhichnegativelyimpacthealthandareassociatedwith (e.g., venlafaxine and duloxetine) [4, 5]. high fnancial costs [1]. According to the World Health Most antidepressant drugs have a delayed onset of ther- Organization, depression will become the primary cause of apeutic actions and many have side efects when taken in disability by 2030 [2]. the long term. Tis has led patients to search for alternatives, A wide variety of antidepressant drugs are available based on the use of plants with reputed antidepressant activity to treat the symptoms of depression. Such antidepressants [6]. An increasing number of studies have investigated natu- produce their therapeutic efects through actions on diverse ralchemicalcompoundswithpotentialantidepressantactiv- neurotransmitter systems, including the serotonergic, nora- ity [7], including bioactive metabolites, such as favonoids, drenergic, and dopaminergic systems [3]. Te principal anti- that exert multiple efects on the central nervous system [8]. depressant drugs are tricyclic antidepressants (e.g., clomi- Substantial preclinical evidence indicates that some fa- pramine and imipramine), monoamine oxidase inhibitors vonoids reduce behavioral endophenotypes of depression in (e.g., phenelzine and selegiline), selective serotonin reuptake animal models by increasing the concentrations of diferent 2 Scientifca

3   2 4 O  B O 8 1  O 5 7 2  OH AC 6 6 3 O O 45 Flavones Flavonols Figure 1: Basic structure of favonoids and the system of numeration. A and B are phenyls, and C corresponds to pyrene. Numbers indicate the numeration system of the basic structure of favonoids. O O

OH neurotransmitters and expression of neurotrophic factors in the brain [9, 10]. Te present review focuses on the results of Flavanones Flavan-3-ols preclinical research that indicate the potential antidepressant efects of some favonoids and describes the mechanisms O O of action that are involved in these efects. We propose future scientifc research in the area of pharmacotherapy to develop safe and efective antidepressant drugs based on OH O natural products to ameliorate the symptoms of depression O in humans. Flavanonol Isofavones 2. Background on Flavonoids Figure 2: General classifcation and basic structure of favonoids. Flavonoids are phenolic compounds that are widely distributed in vascular plants. Many chemical compounds, both enzymethatfacilitatesthehydrolysisoffavonoidsiscytosolic in their free form and in the form of glycosides, have been �-glycosidase, which hydrolyzes a high number of glycosides evaluated to determine their biological activity [11]. More [68, 69]. Cytosolic �-glycosidase is located intracellularly than 5000 types of favonoids have been identifed, which are in erythrocytes; therefore, active transport is required to structurally diferent and possess a wide range of biological cross cellular membranes. It is produced by sodium-glucose activities. Flavonoids are chemical compounds with a low transport protein, which depends on sodium (SGLT-1) [69]. molecular weight whose base structure (Figure 1) comprises Hydrolyzed favonoids (aglycones) are conjugated a system of rings of diphenyl pyrene or phenyl benzopyrene through methylation, sulphatation, and glucuronidation. accompanied by two variable groups of hydroxyl phenolic Because of their high conjugation, hydrolyzed favonoids are radicals [12]. detected in low concentrations in plasma [70]. For example, According to the chemical structure of favonoids (Fig- hesperetin aglycone (the active form of the favonoid ure 2), they can be classifed as favonoids, favones, fa- hesperidin) is metabolized by the cytochrome isoforms P450 vanones, isofavones, and anthocyanidins [62]. Studies in CYP1A and CYP1B1. Tis frst-pass metabolism principally mammals and in vitro have shown that favonoids exert occurs through intestinal cells [71]. Te metabolites of antioxidant, antiallergic, hepatoprotective, antiviral, anticar- hesperidin/hesperetin are eliminated by renal route. Teir cinogenic, neuroprotective, antitoxic, anxiolytic, antiepilep- metabolites are found in urine but not feces, suggesting that tic, estrogenic, and antidepressant-like efects by inhibiting the high bacterial degradation of phenolic acids occurs at the some enzymes [63–66], which is dependent on the dose and level of the colon, allowing passage to the systemic circulation type of favonoid administered. [71]. Particularly, the elimination of the favonoid chrysin depends on the outfow, in which conjugated structures 3. Flavonoid Metabolism are hydrolyzed through sulphatases and glucuronidases in the intestine, suggesting that chrysin has low intestinal Te daily dietary intake of favonoids in humans is approx- absorption, in which it is detected in high concentrations in imately 1-2 g per day, principally depending on individual feces [72]. alimentary habits [67]. Most favonoids are found in plants in Some studies have shown that hydrolyzed favonoids and the �-glycoside form. Afer intake, the processes of hydrolysis their conjugated derivatives may cross the hematoencephalic occur, but since the union-� in these sugars is resistant barrier and exert actions on the central nervous system [73]. to the hydrolysis produced by pancreatic enzymes, this Tis may at least partially explain their multiple pharma- metabolic process occurs in the intestinal lumen through cological actions at the neuronal level that afect cognition actions of the lactase phlorizin hydrolase that is located and emotional and afective states. Numerous preclinical in the membrane of enterocytes. When phlorizin hydro- studies have shown that some favonoids reduce depressive- lase hydrolyzes favonoids, they become capable of crossing like behavior, and these efects are related to the activation of intestinal membranes through passive difusion. Another neurotransmitter systems and trophic factors in the brain. Scientifca 3

Table1:Plantswithantidepressant-likeefectsassociatedwiththeirtotalfavonoidscontent.

Duration of Plant (family) Doses (animal) Behavioral test Reference treatment Alpinia oxyphylla Miq. 10 mg/kg, 14 days FST, SPT [13] (Zingiberaceae) p.o. (A) 400 mg/kg, Single dose TST [14] Hemerocallis citrina L. p.o. (B) (Xanthorrhoeaceae) 10, 20, and 40 mg/kg, 35 days SPT [15] p.o. (C) Apocynum venetum Linn. 0.35 mM/kg, Single dose FST, TST [16] (Apocynaceae) i.p. (B) Hibiscus esculentus L. 500 and 750 mg/kg, Single dose FST, TST [17] (Malvaceae) i.p. (D) Apocynum venetum L. 50 and 100 mg/kg, 10 days FST, TST [18] (Apocynaceae) p.o. (E) Glycyrrhiza uralensis Fisch. 30,100,and300mg/kg, 28 days FST, TST [19, 20] (Fabaceae) p.o. (F) Byrsonima crassifolia (L.) Kunth 500 mg/kg, Single dose FST [21] (Malpighiaceae) p.o. (E) Cecropia pachystachya Trecul´ 50 mg/kg, 8days FST [22] (Urticaceae) p.o. (G) Chrysactinia mexicana A. Gray 1,5,10,100,and200mg/kg, Single dose FST [23] (Asteraceae) p.o. (H) Opuntia fcus-indica (L.) Mill. 30 mg/kg, 14 days FST, TST [24] (Cactaceae) p.o. (E) Hibiscus rosa-sinensis Linn. 30 and 100 mg/kg, Single dose FST, TST [25] (Malvaceae) p.o. (C) Actaea spicata L. 200 mg/kg, Single dose FST [26] (Ranunculaceae) p.o. (I) Clerodendrum serratum Linn. 25 and 50 mg/kg, 7 days FST, TST [27] (Verbenaceae) p.o. (A) Male Kunming mice; (B) male mice; (C) male Sprague-Dawley rats; (D) male Swiss albino mice; (E) male ICR mice; (F) rats; (G) male Wistar rats; (H) male Swiss Webster mice; (I) male LACA mice. FST: forced swim test; TST: tail suspension test; SPT: sucrose preference test.

4. Antidepressant-Like Effects of Flavonoids in poseahealthrisktopatients.Preclinicalstudieshaveevalu- Plant Extracts ated the efects of plant extracts that contain a high percentage of total favonoids (Table 1) that produce antidepressant-like Te treatment of depressive disorders is principally based efects in animal models of depression through actions on on the use of synthetic antidepressant drugs (e.g., tricyclic neurotransmitter receptors and production of neurotrophic antidepressants, selective serotonin reuptake inhibitors, and factorsinthebrain[40]. dual-action antidepressants) that are clinically efective but Behavioral models (e.g., tail suspension test, forced produce side efects. A principal limiting factor in the use swim test, and chronic unpredictable mild stress [CUMS] of antidepressant drugs is their delayed onset of therapeu- paradigm) allow identifcation of the potential antidepres- tic antidepressant efects. Generally, therapeutic efects in sant efects of diverse natural substances as favonoids [78, humans occur afer 2-3 weeks of treatment through neuronal 79], among others. Naringenin (10, 20, and 50 mg/kg), an plastic changes and the modifcation of neurotransmitter isofavone isolated from citrus peel, reduced total immobility receptors. Tis process requires a relatively long time to time in the tail suspension test in male mice, similar to the produce antidepressant efects [74, 75]. In the frst weeks of efects of 20 mg/kg fuoxetine, a clinically efective antide- antidepressant treatment, patients may experience a worse pressant drug. Tese efects were interpreted as potential mood state compared with their state before the initiation of antidepressant-like efects [52]. Interestingly, this efect was pharmacological treatment [76]. Patients have sought ther- blocked by pretreatment with p-chlorophenylalanine methyl apeutic alternatives to ameliorate symptoms of depression. ester (100 mg/kg) and �-methyl-p-tyrosine (100 mg/kg), Infusions or standardized extracts of plants have been used inhibitors of the synthesis of serotonin and norepinephrine, for the alternative treatment of depression [77]. However, respectively [52]. Tis suggests that the mechanism of in most cases, these alternative therapies have not been action of naringenin involves the activation of serotonergic investigated in systematic studies to support or refute their and noradrenergic neurotransmitter systems in the brain. purported medicinal properties. Such a dearth of studies can Additionally, 10 and 20 mg/kg naringenin increased the 4 Scientifca expression of brain-derived neurotrophic factor (BDNF) in the levels of proinfammatory cytokines in the brain [90], the hippocampus afer 21 days of treatment in mice that apparently by its high content of favonoids. A reduction of were subjected to CUMS [28], which was associated with immobility time in the forced swim test was also produced an antidepressant-like efect. Tese results indicate that the by acute or chronic administration of 30, 100, and 300 mg/kg antidepressant-like efect of naringenin may be mediated of aqueous [91] or ethanolic [92] extracts of Melissa ofc- by the activation of both neurotransmitter systems and inalis L. (Lamiaceae). Tis same efect was produced by neurotrophic factors. Such mechanisms of action have also its active metabolite rosmarinic acid (36 mg/kg) in male been identifed for other clinically efective antidepressant Sprague-Dawley rats [91], and the authors suggested that the drugs, such as fuoxetine [80]. antidepressant-like efect of this extract could be associated Park et al. (2006) [81] found that a standardized extract with its high content of rosmarinic acid, which is able to mod- of Cirsium japonicum Fisch. ex DC (Asteraceae) produced ulate the serotonergic system [91]. However, it is not possible antidepressant-like efects in male mice. Tis efect was repli- to discard the participation of other chemical constituents of cated in subsequent studies that evaluated the antidepressant- the M. ofcinalis extracts in their antidepressant-like efects, like efect of an ethanolic extract of this plant at doses considering the high content in essential oils and favonoids of 50, 100, 200, and 400 mg/kg and its principal chemical such as quercitrin, apigenin, and luteolin derivatives that constituents (i.e., linarin, pectolinarin, chlorogenic acid, and may inhibit monoamine oxidases A (MAO-A) activity and luteolin) at doses of 10 mg/kg in the forced swim and open interact with the GABAA receptors [93], which also occurs feld tests [30]. Te authors showed that the antidepressant- with the majority of the conventional antidepressant drugs like efects of this plant extract were produced by the [94]. favonoid luteolin through actions on the GABAA receptor. Glycyrrhiza uralensis Fisch. (Fabaceae) is another plant Such GABAA receptoractivationhasalsobeeninvolvedinthe with potential antidepressant-like efects that are associated antidepressant-like activity of other plant metabolites [82, 83] with its content of at least fve favonoids (i.e., liquir- � and some neurosteroids such as allopregnanolone [84–86]. itin, liquiritigenin, isoliquiritigenin, isoononin, and 7,4 - In male Sprague-Dawley rats, CUMS and an acute injec- dihydroxyfavone). An extract of this plant inhibited the tion of corticosterone were used to produce depression- production of tumor necrosis factor-� (TNF-�)inmicroglial like behavior. Te antidepressant-like efects of the favonoid cells in mice [95]. Tese fndings are important because TNF- icariin (60 mg/kg), isolated from Epimedium brevicornum � has been detected in high concentrations in patients with Maxim (Berberidaceae) on depression-like behavior pro- anxiety and depression symptoms. Terefore, a reduction of duced by CUMS or corticosterone injection, were evaluated TNF-� could be benefcial for ameliorating symptoms of anx- in the forced swim test. Corticosterone and CUMS increased iety and depression, as is the case with other antidepressant total immobility time, refecting despair-like behavior, and agents. Te favonoid isoliquiritigenin also inhibits TNF-� reduced BDNF concentrations in the hippocampus. Tese and increases the concentration of BDNF in the hippocampus efects were prevented by the administration of icariin and cerebral cortex [95]. Administration of the favonoid 5,7- favonoid, which was associated with the antidepressant-like dihydroxyfavone (chrysin) at doses of 1 and 10 mg/kg for efect [32]. 60 days increased BDNF concentrations in the hippocampus A preclinical study of the methanolic extract of Byrsonima and prefrontal cortex [96] and produced antidepressant-like crassifolia (L.) Kunth (Malpighiaceae) at a dose of 500 mg/kg efects in the forced swim test in mice [10]. Tese data are reported an antidepressant-like efect that was similar to the relevant because higher plasma and brain concentrations of clinically efective antidepressant imipramine in albino ICR BDNF were detected when clinically efective antidepressant mice in the forced swim test. Te authors indicated that drugs were administered in experimental animals (for review, this antidepressant-like efect was attributable to favonoids see [97]) and depressed patients (for review, see [80]), in the extract [21], corresponding to quercetin (1.4 mg/kg), suggesting that favonoids have a similar pharmacological rutin (4.4 mg/kg), and hesperidin (0.7 mg/kg), which pro- profle as conventional antidepressant drugs. duce antidepressant-like efects when they are individually Su et al. (2014) [98] evaluated the efects of the Chinese injected [9, 54, 87, 88]. Additionally, it has been reported herbal formula Xiao Chai Hu Tang,whichcontainsparts that the administration for 7 days of favonoid quercetin from plants described as Radix Bupleuri Chinensis, Radix (10, 50, and 200 mg/kg, p.o.) decreases the 5-hydroxyindole Scutellariae Baicalensis, ginseng, Rhizoma Pinelliae Ternatae, acetaldehyde production modulating the serotonergic system Radix Glycyrrhiza Uralensis, Rhizoma Zingiberis Recens, by attenuating mitochondrial MAO-A activity in the brain and Fructus Jujubae. Tis herbal preparation contains a [89], which is involved in the therapeutic efect of some high percentage of favonoids, glycosylated favonoids, and antidepressant drugs. saponins. Te authors tested the efects of administration of Oral administration of 25, 50, and 100 mg/kg of a 0.6, 1.7,and 5 mg/kg for 4 weeks. Te extract was administered standardized aqueous extract, referred to as Xiaobuxin- in male Sprague-Dawley rats subjected to CUMS, and the Tang, which contains four diferent natural products (i.e., efects were evaluated in the open feld test; glucose pref- Haematitum, Flos Inulae, Folium Phyllostachydis Henonis, erence and consumption and food consumption were also and Semen Sojae Preparatum), reduced immobility time evaluated. Te results showed that CUMS reduced glucose in both the forced swim and the tail suspension tests in preference and food consumption, refecting anhedonia, lipopolysaccharide-treated ICR mice, thus demonstrating which is a principal symptom in depressed patients. Interest- an antidepressant-like efect. Xiaobuxin-Tang also reduced ingly, these deleterious efects of CUMS were prevented by the Scientifca 5 herbal preparation Xiao Chai Hu Tang,whichwasassociated allowing plastic changes and subsequently the therapeutic with higher levels of BDNF, nerve growth factor (NGF), efects of antidepressant drugs [105]. Preclinical research has and tropomyosin receptor kinase A (TrkA) and tropomyosin also investigated the efects of specifc favonoids that are receptor kinase B (TrkB) in the hippocampus [98]. extracted from medicinal plants. Tese favonoids have been Another study explored the efects of a standardized purifed, chemically characterized, and prepared for adminis- extract used in traditional Chinese medicine. Tis herbal tration. Such eforts have allowed the identifcation of specifc preparation, Xiaobuxin-Tang, includes Flos Inulae, Folium favonoids that have potential antidepressant-like efects. Phyllostachydis Henonis,andSemen Sojae Preparatum and contains a high percentage of favonoids. A dose of 100 mg/kg 5. Antidepressant-Like Effects of of this extract produced antidepressant-like efects in male Flavonoids Isolated from Plants ICR mice, which were blocked by pretreatment with l- arginine (750 mg/kg), a precursor of nitric oxide synthesis. Flavonoids produce pharmacological actions on the central Coadministration of 7-nitroindazole (50 mg/kg), an inhibitor nervous system (Table 2) to regulate emotional and mood of nitric oxide synthesis, potentiated the action of an states associated with plastic and neurochemical changes as inefective dose of Xiaobuxin-Tang (50 mg/kg) to produce is the case with conventional antidepressant drugs [9, 10, 38, antidepressant-like efects [41]. Tese fndings suggest that 101]. the antidepressant-like efect of this extract involves nitric Preclinical studies have also reported the potential oxide signaling. A similar mechanism has been reported for antidepressant-like efects of specifc favonoids (Table 3). lamotrigine, which also has antidepressant-like activity [99]. Hesperidin is a favonoid that has diferent pharmacological Apocynum venetum L. (Apocynaceae) extract produces actions (e.g., antioxidant, antineoplastic, and neuroprotective antidepressant-like efects in male CD rats subjected to efects) in vitro and in vivo. Tis favonoid has been studied as the forced swim test, apparently by their high content of a potential antidepressant agent because of its actions on the hyperoside and isoquercitrin which are major favonoids in serotonergic, dopaminergic, and noradrenergic systems. Te the extract [100]. Diferent doses (25, 50, and 100 mg/kg) of an administration of 0.1, 0.3, and 1 mg/kg hesperidin (i.p.) for Apocynum venetum L. extract that contained a high percent- 21 days in Swiss mice signifcantly reduced total immobility age of favonoids were also evaluated in male ICR mice [18]. time in the tail suspension test. Tis antidepressant-like Te 50 and 100 mg/kg doses signifcantly reduced immobility efect was associated with a signifcant increase in BDNF time in both the forced swim test and the tail suspension test, concentrations in the hippocampus [9] and actions at the without producing nonspecifc efects on motor activity in 5-HT1A receptors [106]. Also, the administration of 10, 20, the open feld test, a typical efect of substances with antide- and 40 mg/kg astilbin (i.p.) for21daysinmaleC57BL/6Lmice pressant activity [101]. Tese antidepressant-like efects were exerted antidepressant-like efects in the forced swim test, tail associated with higher concentrations of norepinephrine and suspension test, and CUMS paradigm, and these efects were dopamine and their metabolites 3,4-dihydroxyphenylacetic associated with an increase in BDNF concentrations in the acid (DOPAC) and homovanillic acid (HVA), respectively, cerebral cortex. Tese efects were similar to those produced in the hippocampus. Furthermore, these antidepressant-like by 10 mg/kg of the tricyclic antidepressant imipramine [34]. efects were blocked by pretreatment with the dopamine Te behavioral and molecular efects of the favonoid D1 receptor antagonist SCH23390 (0.05 mg/kg) and D2/3 baicalein (40 mg/kg, i.p., for 14 days) were evaluated in male receptor antagonist sulpiride (50 mg/kg) [18], confrming Sprague-Dawley rats. Baicalein signifcantly reduced total that the antidepressant-like efects of Apocynum venetum L. immobility time, similar to the antidepressant fuoxetine, occur through actions on the dopaminergic system. Tis in the forced swim test. Tis antidepressant-like efect was mechanism of action is important because clinically efec- associated with activation of the dopaminergic system and tive antidepressant drugs, such as clomipramine (tricyclic greater expression of BDNF mRNA in the hippocampus, an antidepressant) and fuoxetine (selective serotonin reup- efect also detected with the antidepressant fuoxetine [35]. take inhibitor), activate the serotonergic and noradrenergic In support, injections of baicalein (1, 2, and 4 mg/kg,i.p., systems in the long term and parallelly also activate the for 21 days) in male Kunming mice subjected to CUMS mesolimbic dopamine system producing their antidepressant reducedimmobilitytimeintheforcedswimandtailsus- efects [102–104]. pension tests, which was accompanied by an increase in Te aforementioned data show that favonoids and likely extracellular signal-regulated kinase and BDNF expression in other active metabolites that are contained in plant extracts the hippocampus, similar to 15 mg/kg of the antidepressant may contribute to the antidepressant-like efects of plants imipramine [36]. that are used in traditional medicine to ameliorate symp- Another favonoid, baicalin, isolated from the dried toms of depression. Tese benefcial efects appear to occur root of Scutellaria baicalensis Georgi (Labiatae), produces through the activation of neurotransmitter systems and other an antidepressant-like efect in the forced swim and tail neuronal processes. Te activation of neurotrophic factors, suspension tests in mice treated with 25 and 50 mg/kg, p.o. such as BDNF, signifcantly impacts neuronal function. Tis efect was similar to that produced by 20 mg/kg of the Te activation of neurotransmitter systems (i.e., principally antidepressant fuoxetine. Apparently, the baicalin efect was serotonergic, noradrenergic, and dopaminergic) in specifc associated with inhibition of monoamine oxidase enzymes brain areas (e.g., hippocampus and prefrontal cortex) reac- types A and B [107], a mechanism of action involved in the tivates chemical communication in the long term, thus therapeutic efect of some antidepressant drugs. 6 Scientifca

Table 2: Neurobiological efects produced by some favonoids.

Treatment Flavonoid Doses Efects Reference duration Increase in BDNF concentrations in the 5, 10, and 20 mg/kg 21 days [28] hippocampus in male mice Naringenin Increase in 5-HT, DA, and NE in the 5,10,and20mg/kg 14days [29] hippocampus in male ICR mice

30 min before Increases in chloride ion fow at the GABAA 10 mg/kg [30] test receptor in male rats Luteolin Attenuation of the expression of endoplasmic [31] 50 mg/kg 23 days reticulum stress-related proteins in the hippocampus in male ICR mice Increases in BDNF concentrations in the Icariin 60 mg/kg 21 days [32] hippocampus in male rats Increase in BDNF concentrations in the 0.01, 0.1, 0.3, and 1 mg/kg 21 days [9] hippocampus in male mice Hesperidin Increase in BDNF and NGF concentrations in the 50 mg/kg 13 days [33] hippocampus in male C57BL/6 mice Increase in BDNF concentrations in the cerebral Astilbin 10, 20, and 40 mg/kg 21 days [34] cortex in male mice, similar to imipramine Increase in dopamine and BDNF concentrations 10, 20, and 40 mg/kg 14 days [35] in the hippocampus in male rats Baicalein Restoring of the reduction of extracellular Single injection signal-regulated kinase phosphorylation and 1and4mg/kg [36] or 21 days BDNF expression in the hippocampus of male Kunming mice subjected to CUMS Increase in BDNF concentrations in the 5and20mg/kg 28days hippocampus and prefrontal cortex in female [10] mice Chrysin Increase in 5-HT and BDNF concentrations in the 5and20mg/kg 14days [37] hippocampus in male C57B/6J mice Activation of the serotonergic system, apparently 60 min before 5, 10, and 20 mg/kg through inactivation of MAO-A enzyme in male [38] test mice Fisetin Increases in phosphorylated TrkB (pTrkB) in the 5 mg/kg 14 days [39] hippocampus in male ICR mice Increase in BDNF, serotonin, and norepinephrine Orientin 20 and 40 mg/kg 21 days concentrations in the hippocampus and prefrontal [40] cortex in male mice 60 min before Increase in BDNF concentrations in the 7,8-Dihydroxyfavone 1, 3, and 10 mg/kg [41] test hippocampus and prefrontal cortex in male mice Decrease in oxidative stress and Icariin 20 and 40 mg/kg 35 days neuroinfammation in the hippocampus in male [42] rats Increase in mRNAforBDNFinthehippocampus Dihydromyricetin 10 and 20 mg/kg 7 days [43] in male C57BL/6 mice Increase in 5-HT, DA, NE, and BDNF Silymarin 100 and 200 mg/kg 14 days concentration in the hippocampus and cerebral [44] cortex, similar to fuoxetine in adult Wistar rats Increases in cell proliferation in the subgranular Myricitrin 10 mg/kg 21 days zone of the hippocampal dentate gyrus in male [45] BALB/c mice Increases in BDNF concentrations in the Myricetin 50 mg/kg 21 days [46] hippocampus in male C57BL/6 mice � � Increase in BDNF concentration, neurogenesis, 3,5,6,7,8,3 ,4 - 50 and 100 mg/kg 15 days and neuroplasticity in the hippocampus in male [47, 48] Heptamethoxyfavone C57BL/6 mice Scientifca 7

Table 2: Continued. Treatment Flavonoid Doses Efects Reference duration Increase in BDNF concentrations in the Apigenin 20 and 40 mg/kg 21 days [49] hippocampus in male ICR mice Modulation of the hypothalamic-pituitary-adrenal axis by reducing Miquelianin 0.6 mg/kg 14 days [50] plasma concentration of ACTH and corticosterone in male CD rats Modulation of the hypothalamic-pituitary-adrenal axis by reducing Isoquercitrin 0.6 mg/kg 14–56 days [50] plasma concentration of ACTH and corticosterone in male CD rats Liquiritin and 30 min before Increases in 5-HT and NE concentrations in the 20 mg/kg [51] isoliquiritin sample hippocampus, hypothalamus, and cortex in mice BDNF: brain-derived neurotrophic factor; NGF: nerve growth factor; MAO-A: monoamine oxidase type A; TrkB: tropomyosin receptor kinase B; 5-HT: serotonin; DA: dopamine; NE: norepinephrine; ACTH: adrenocorticotropic hormone.

Te administration of 10, 20, 30 mg/kg of the favonoid Other favonoids with antioxidant, anti-infammatory, vitexin (p.o.) also signifcantly reduced total immobility and neuroprotective efects have also been evaluated as time in both the forced swim and the tail suspension potential antidepressant agents, one example of which is tests. Interestingly, animals treated with vitexin exhibited the favonoid fsetin. Te administration of 10 and 20 mg/kg a signifcant increase in the time spent climbing in the fsetin (i.p.) signifcantly reduced total immobility time forced swim test [53], suggesting that activation of the in the forced swim and tail suspension tests [38]. Tis noradrenergic system may be involved in the antidepressant- antidepressant-like efect was apparently produced by acti- like efect of this favonoid. A selective increase in the time vation of the serotonergic system. Te blockade of sero- spent climbing is only produced by antidepressant drugs tonin synthesis by pretreatment with p-chlorophenylalanine that act on the noradrenergic system [108]. Injections of the blocked the antidepressant-like efect of fsetin. Tis study serotonin 5-HT1A receptor antagonist 1-(2-methoxyphenyl)- also found that fsetin inhibited the activity of MAO-A, 4-(4-[2-phthalimido]butyl)-piperazine (NAN-190) or which is involved in the metabolism of serotonin and dopamine receptor antagonist SCH23390 blocked the norepinephrine [38]. Similarly to other favonoids, fsetin antidepressant-like efect of vitexin [53], indicating that seems to exert its antidepressant-like efects through at the antidepressant-like efects involve the activation of at least two diferent mechanisms of action: activating the least three neurotransmitter systems (i.e., serotonergic, serotonergic system and inhibiting monoamine metabolism. noradrenergic, and dopaminergic). Similarly, the favonoid However, other neurotransmitter systems could be involved nobiletin (25, 50, and 100 mg/kg, p.o.), isolated from in the antidepressant-like efect produced by favonoids. � � citrus peels, produces antidepressant-like efects in the Two synthetic favones, 3 -methoxy-6-methylfavone and 3 - forced swim and tail suspension tests in male ICR mice. hydroxy-6-methylfavone, in doses of 100 mg/kg, i.p.,pro- Interestingly, these efects are blocked by previous injection duce antidepressant-like efects in the forced swim and of WAY 100635 (a serotonin 5-HT1A receptor antagonist), tail suspension tests, similar to antidepressant imipramine cyproheptadine (a serotonin 5-HT2A receptor antagonist), [114]. Interestingly, the efect produced by both synthetic prazosin (an �1-adrenoceptor antagonist), SCH23390 (a favonoids was partially ameliorated by coadministration of dopamine D1 receptor antagonist), or sulpiride (a dopamine bicuculline (a competitive �-aminobutyric acid binding site D2 receptor antagonist), showing that the antidepressant-like antagonist), suggesting the modulation/direct activation of efect of nobiletin involves participation of serotonergic, the GABAA receptors, as is the case with neurosteroids with noradrenergic, and dopaminergic systems [109], as is the antidepressant-like activity [85, 86]. case as well with biofavonoid apigenin in several brain Depressive disorders are highly prevalent in diabetic structures [59]. Tis multiple mechanism of action is patients. Using a preclinical model of diabetes that was unsurprising. Te administration of standardized herbal induced by streptozotocin in mice, the efects of the biofa- products or phytomedicines prepared with Hypericum vonoid quercetin (50 and 100 mg/kg, i.p.)werecompared perforatum L. (Hypericaceae) extracts activates multiple with fuoxetine (5 mg/kg, i.p.) and imipramine (15 mg/kg, neurotransmitter systems and produces both preclinical i.p.) in the forced swim test [115]. Results showed that and clinical antidepressant efects [110–112]. However, these quercetin signifcantly reduced depressive-like behavior in multiple actions have been associated with some severe side diabetic mice, similar to the conventional antidepressants fu- efects [113]. Further studies are necessary to explore the oxetine and imipramine. Interestingly, the quercetin-induced multiple actions of favonoids in the brain under diferent reduction of depressive-like behavior was only detected in experimental conditions (e.g., acute or chronic treatment) to diabetic mice and not in healthy mice, while fuoxetine identify potential side efects to ensure consumer safety. and imipramine produced antidepressant-like efects in both 8 Scientifca [9] [31] [51] [51] [51] [51] [61] [10] [10] [41] [41] [53] [53] [32] [55] [35] [32] [52] [52] [57] [58] [59] [38] [38] [24] [28] [24] [24] [24] [29] [34] [34] [56] [34] [30] [36] [54] [54] [36] [42] [42] [60] [40] [40] [40] Reference Efect No efect Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant mice. (E) Adult male Wistar rats. (F) Adult male 6J mice. (K) Mice sex and strain were not identifed. (L) antidepressant-like efect is suggested by the increase in sucrose The 2 21 days 21 days 21 days 21 days 21 days 21 days 21 days 21 days 21 days 21 days 21 days 21 days 14 days 14 days 14 days 14 days 14 days 14 days 14 days 14 days 14 days 35 days 35 days 35 days 23 days 28 days 28 days 28 days 49 days 30 min before test 30 min before test 30 min before test 30 min before test 30 min before test 60 min before test 60 min before test 60 min before test 60 min before test 60 min before test 60 min before test 60 min before test 60 min before test Treatment duration 21, 18, and 1 h before test Antidepressant Single injection or 21 days Antidepressant Single injection or 21 days Antidepressant i.p. i.p. i.p. i.p. p.o. p.o. p.o. p.o. p.o. p.o. p.o. p.o. i.p. p.o. p.o. p.o. i.p. i.p. i.p. i.p. i.p. p.o. p.o. p.o. p.o. p.o. p.o. p.o. i.p. p.o. p.o. p.o. i.p. p.o. p.o. p.o. i.p. p.o. p.o. p.o. p.o. p.o. p.o. p.o. p.o. Doses 50 mg/kg, 10 mg/kg, 30 mg/kg, 30 mg/kg, 30 mg/kg, 30 mg/kg, 50 mg/kg, 60 mg/kg, 60 mg/kg, 3 and 10 mg/kg, 7 and 14 mg/kg, 5 and 20 mg/kg, 5 and 20 mg/kg, 10 and 20 mg/kg, 15 and 30 mg/kg, 10 and 20 mg/kg, 1, 2, and 4 mg/kg, 1, 2, and 4 mg/kg, 25 and 50 mg/kg, 20 and 40 mg/kg, 20 and 40 mg/kg, 20 and 40 mg/kg, 20 and 40 mg/kg, 20 and 40 mg/kg, 20 and 40 mg/kg, 40 and 80 mg/kg, 50 and 100 mg/kg, 50 and 100 mg/kg, 1, 3, and 10 mg/kg, 5, 10, and 20 mg/kg, 5, 10, and 20 mg/kg, 5, 10, and 20 mg/kg, 0.1, 0.3, and 1 mg/kg, 10, 20, and 40mg/kg, 10, 20, and 40mg/kg, 10, 20, and 40mg/kg, 10, 20, and 40 mg/kg, 10, 20, and 50 mg/kg, 10, 20, and 30 mg/kg, 10, 20, and 50 mg/kg, 10, 20, and 30 mg/kg, 10, 20, and 40 mg/kg, 10, 20, and 40 mg/kg, 10, 20, and 40 mg/kg, 10, 20, and 40 mg/kg, Table 3: Efect of favonoids on depression-like behavior at preclinical research. O -rutinoside (A) Icariin (B) Icariin (B) Icariin (B) Fisetin (A) Fisetin (A) Chrysin (J) Chrysin (J) Vitexin (D) Vitexin (D) Astilbin (C) Astilbin (C) Astilbin (G) Orientin (F) Orientin (F) Orientin (F) Luteolin (A) Baicalein (F) Naringin (E) Baicalein (F) Baicalein (B) Apigenin (A) Quercetin (I) Liquiritin (K) Liquiritin (K) Quercetin (L) Quercetin (E) Quercitrin (A) Quercitrin (A) Hesperidin (H) Naringenin (A) Naringenin (A) Naringenin (A) Kaempferol (A) Kaempferol (A) Isoliquiritin (K) Isoliquiritin (K) Flavonoid (animal) 7,8-Dihydroxyfavone (G) 7,8-Dihydroxyfavone (G) 7,8-Dihydroxyfavone (G) Isosakuranetin-5- 2 1 1 antidepressant-like efect is suggested by the reduction in immobility time without signifcant changes in the general locomotor activity. The Model of depression Forced swim test Tail suspension test CUMS-sucrose intake 1 Kunming mice. (G) Adult male C57BL/6 mice. (H) Adult male Swiss mice. (I) Male 21-day streptozotocin-induced diabetic Wistar rats. (J) Female C57BL/ intake. CUMS: chronic unpredictable mild stress. (A) Adult maleFemale ICR Swiss mice. mice. (B) Male Sprague-Dawley rats. (C) Male C57BL/6J mice. (D) Adult male BALB/c Scientifca 9 diabetic and healthy mice. In another study, quercetin that the antioxidant activity and the activation of monoamin- (50 mg/kg, i.p., for 21 days) also exerted antidepressant-like ergic systems are associated with the production of BDNF efects in diabetic rats in the forced swim test. Tese efects by favonoids [119], ultimately producing antidepressant-like did not involve regulation of the hypothalamic-pituitary- efects in animals. However, this hypothesis requires further adrenal axis, in which this favonoid did not produce sig- exploration. nifcant changes in plasma adrenocorticotropic hormone or corticosterone concentrations [54]. Tese data suggest that 6. Concluding Remarks quercetin may have a mechanism of action that is diferent from conventional antidepressants. Te antidepressant-like Preclinical data on the antidepressant-like efects of some efects of quercetin have been suggested to primarily occur favonoids have consistently reported behavioral efects and through antioxidative actions and a reduction of proinfam- neurochemical actions in the brain, thus supporting the matory cytokine concentrations in the brain [54] that in the potential therapeutic application of these natural compounds long term restore neurochemical function as is the case with for the amelioration of depressive symptoms in humans. conventional antidepressant drugs. Future studies should Te data that were reviewed herein implicate BDNF in the explore the ability of quercetin to ameliorate symptoms of antidepressant-like efects of favonoids. Tis mechanism of depression, particularly in diabetic patients. action is relevant because it has been associated with the Finally, studies of the neurobiological bases of depressive actions of clinically efective antidepressant drugs [80, 120]. disorders and mechanisms of action of antidepressant drugs BDNF modulates neurotransmitters and receptor activity and have shown that reductions of neurotransmitter system activ- is involved in the activation of serotonergic, noradrenergic, ity and BDNF concentrations are associated with depressive and dopaminergic pathways and neurogenesis in the hip- symptoms in humans [116] and depression-like behavior in pocampus and cerebral cortex, which are implicated in the stressor-exposed rats [42]. A reduction of BDNF synthesis neurobiology of psychiatric disorders, including depression. has been observed in the hippocampus and cerebral cortex, Activation of BDNF and TrkB is produced afer admin- among other brain structures, in experimental animals. istration of conventional antidepressant drugs, such as fu- Antidepressant drugs increase BDNF production in both ani- oxetine and citalopram [28, 101, 121], which is associated mals and depressed patients [97, 117], suggesting a negative with the reduction of most of the symptoms of depression correlation between BDNF concentrations and the severity [97, 122–124]. Some favonoids (e.g., 7,8-dihydroxyfavone) of depressive symptoms. alsoactasTrkBreceptoragonistsandstimulateneurogenesis Mice that are subjected to CUMS develop symptoms in the hippocampus [41]. Such fndings may reveal new of anhedonia (e.g., a reduction of sucrose preference and possibilities for the development of therapeutic alternatives consumption) and depressive-like behavior (e.g., increase in for the treatment of depression, including the administration immobility time in the forced swim test), and these efects of subthreshold doses of favonoids combined with conventional antidepressant drugs. Combined administration were prevented by oral administration of 5 and 20 mg/kg of both substances could likely produce antidepressant-like of the favonoid chrysin afer 28 days of treatment. Tis efects with a shorter onset of action through the early antidepressant-like efect of chrysin was accompanied by stimulation of BDNF production and parallelly modify the an increase in BDNF concentrations in the hippocampus neurotransmitter receptor function, which requires further andprefrontalcortexandtheactivationofNGFinmice exploration. [10]. Additionally, favonoid chrysin (5 and 20 mg/kg, p.o., Finally, despite the positive fndings regarding the 28 days), similar to antidepressant fuoxetine (10 mg/kg, p.o., antidepressant-like efects of some favonoids at the preclin- 28 days), increases serotonin concentration and reduces the ical level, potential side efects of long-term consumption indoleamine-2,3-dioxygenase and caspases 3 and 9 activi- need to be investigated, including studies of toxicology and ties in the prefrontal cortex and hippocampus in C57B/6J possible pharmacological interactions with other substances, mice subjected to CUMS, which was associated with the to determine the tolerability and safety of favonoids in antidepressant-like efect detected in the tail suspension humans. Such studies may eventually demonstrate that some test [118], with the participation of BDNF. Similarly, the favonoids are safe alternatives for the treatment of depressive administration of 20 and 40 mg/kg of the favonoid orientin disorders in clinical practice. for 21 days also produced antidepressant-like efects in mice that were subjected to CUMS, and this efect was associated Conflicts of Interest with the activation of BDNF and an increase in serotonin and norepinephrine concentration in the hippocampus and cere- Te authors declare that there are no conficts of interest. bral cortex [40]. Te administration of 20 and 40 mg/kg of the favonoid icariin for 35 days also produced antidepressant- Acknowledgments like efects in rats that were subjected to CUMS. In that study, Te authors would like to thank Michel Arends for revis- control animals presented signifcant neuronal damage and ing and editing the English of this manuscript. Leon´ neuroinfammation in the hippocampus, which were asso- Jesus´ German-Ponciano and Gilberto Uriel Rosas-Sanchez´ ciated with higher oxidative stress. Tese deleterious efects received fellowships from Consejo Nacional de Ciencia y were reversed by the administration of icariin at doses that Tecnolog´ıa (CONACyT) for postgraduate studies in neu- reduced depressive-like behavior [42]. Tese studies suggest roethology (Reg. nos. 297560 and 592165, resp.). 10 Scientifca

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