Flavonoids, a group of polyphenolic structures, are found abundantly in plants, especially fruits, vegetables, and medical herbs (Moon, Wang, and Morris, 2006). They are well known for their antioxidant activity as a dietary component (Kumar and Pandey, 2013). Furthermore, flavonoids are effective in many diseases with different mechanisms; for example, anticholinesterase activity in Alzheimer’s disease (AD) and steroidogenesis modulators in hormone-dependent cancer (Panche, Diwan, and Chandra, 2016a).

The main focus of some existing reviews (Ali S. et al., 2021; Jia et al., 2022; Khan et al., 2018; Ko et al., 2020; Pannu A. et al., 2021) are animal or human studies, however, the possible mechanisms have not been sufficiently investigated. In an article by Lucian Hritcu et al. (Hritcu et al., 2017a), animal.

Studies in the last 6 years are included. In a study published by Pannu et al. (Pannu Arzoo et al., 2021), only preclinical studies were included, and the effect of flavonoids on human studies was not examined. Other studies, such as clinical trials, found significant results of flavonoids on depression symptoms (Atteritano et al., 2014; Zarghami et al., 2018; Ali Sawan et al., 2021). In an article published by Yong-Hyun Ko et al. (Ko et al., 2020), other types of flavonoids were examined, while one of the most prominent features of the present article, as far as we know, is that none of the existing pieces in this field has examined all the groups and subgroups of flavonoids and their mechanisms as much as this study. The summary of the antidepressant properties of flavonoids is shown in Supplementary Table S1. Flavonoids can be broadly classified according to the carbon located in the B ring’s connection to the C ring. By the structural characteristics of the C ring, the flavonoids linked in position 3 of the C ring are known as isoflavones, those linked in position 4 are neoflavonoids, and those related to position two are divided into various subgroups (chalcones, anthocyanins, flavanols, flavanonols, flavanones, flavonols, and flavones) (Ramesh et al., 2021; Khan et al., 2021).

Apple peels, rich in phloridzin (Dhalaria et al., 2020), might offer a novel approach to managing depression. A study by (Kamdi, Raval, and Nakhate, 2021) suggests phloridzin improves mobility in diabetic mice, a behavioral indicator of reduced depression symptoms. Notably, phloridzin treatment also reversed the decrease in key biochemical markers associated with depression (GSH, BDNF, TrkB, CREB, ERK). These findings warrant further investigation into phloridzin’s potential as a therapeutic strategy for depression, particularly in diabetic patients.

A new study by Zhao et al. suggests DHIPC (2,4-dichloro-2′-hydroxyl-4′,6′- diisoprenyloxychalcone), a synthetic chalcone compound, may hold promise for treating depression (Starchenko et al., 2020). In mice, oral DHIPC significantly reduced immobility time in behavioral tests, suggesting antidepressant effects. This improvement coincided with increased levels of key neurotransmitters (serotonin, noradrenaline, and 5-HIAA) in brain regions associated with mood regulation. (Zhao et al., 2018). These findings warrant further investigation of DHIPC’s potential as a therapeutic option for depression.

Preclinical studies suggest that dietary sources rich in anthocyanins, such as purple cauliflower, pomegranate, and blueberry, may possess antidepressant properties in mice. These studies demonstrate that cyanidin extracts can elevate levels of monoamine neurotransmitters (NE, DA, and 5-HT) through various mechanisms, including inhibition of monoamine oxidase (MAO) activity and increased brain-derived neurotrophic factor (BDNF) production. These effects ultimately contribute to neurogenesis and dendritic growth in the hippocampus, potentially leading to reversal of depressive behaviors. (Fang et al., 2020). Punica granatum methanolic pulp and peel extracts, which are rich in anthocyanins including cyanidin, delphinidin, and malvidin, were administered in male mice at doses of 25 and 50 mg/kg along with fluoxetine as the standard drug (20 mg/kg), respectively. This drug was introduced as a suitable antidepressant by reducing the immobility time in the forced swimming test (Abdul rahman et al., 2015). Blueberry contains various compounds such as Quercetin (QE), malvidin, and anthocyanidin. Gapski et al. (2019) found that blueberry extract could treat neurodegenerative diseases by modulating oxidative stress in the hippocampus. Administration of blueberry extract with doses higher than 300 mg/kg reduced the immobility time of mice in the tail suspension test (TST). Additionally, research suggests that cyanidin, a specific anthocyanin, may exert its antidepressant effects through the PI3K/AKT/FoxG1/FGF-2 pathway, which plays a critical role in neurogenesis (Shan et al., 2020). Other reported changes that attributed to the improved behaviors were restoration of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glutamate-aspartate transporter (GLAST) and excitatory amino acid transporter 2 (EAAT2) expression (Qu et al., 2022). These findings collectively support the exploration of anthocyanin-rich dietary interventions as a potential strategy for managing depression.

The effect of maqui berry extract (MBE) (25,50, and 100 mg/kg) containing cyanidin and delphinidin was investigated on post-stroke depressed male mice for 7 days. Treatment with MBE mitigated anhedonia and immobility time observed in mice. Interestingly, MBE led to a reduction of high levels of TBARS as well as an increase of antioxidant enzymes (Abdul rahman et al., 2015). Therefore, modulating oxidative stress could restore normal behavior in mice (Di Lorenzo et al., 2019).

Malvidin is an anthocyanin obtained from red wine that is proven to protect against oxidative neuronal damage in both animal cell lines and in vivo models (Khoo et al., 2017). Administration of malvidin-3′-O-glucoside was found to attenuate the depressive-like behavior through its ability to cross the BBB and upregulation of Rac1 expression in the nucleus accumbens (Wang et al., 2018), a protein whose depletion contributes to the disturbed synaptic structure in depression (Golden et al., 2013).

Rutin, a citrus bioflavonoid, has emerged as a potential candidate for treating depression based on preclinical studies. (Pandey and Rizvi, 2009). Machado et al. demonstrated that the antidepressant-like effect of an ethanolic extract from Schinus molle, containing rutin, is likely mediated by increased synaptic availability of noradrenaline and serotonin. This finding suggests a potential mechanism for rutin’s action. (Machado et al., 2008). Yusha’u et al. (2017) further supported rutin’s antidepressant potential by observing a dose-dependent decrease in immobility time during the tail suspension test (TST) in mice treated with rutin (Yusha’u et al., 2017) (Figure 3). However, Scheggi et al. reported an inverted U-shaped dose response for rutin’s anti-stress effects, suggesting the existence of an optimal dosage for its efficacy (Scheggi et al., 2016). Similarly, Nöldner and Schötz (2002) observed a threshold effect for rutin’s contribution to the antidepressant properties of Hypericum perforatum extracts.

In a study by (Sommer and Harrer, 1994) one hundred and five outpatients with mild depression for a short period were administered either 3 × 300 mg hypericum extract or a placebo in 4 weeks. In the active group, 28 of 42 patients (67%) and, in the placebo group, 13 of 47 patients (28%) responded to treatment. The medicinal suitability of an antidepressant is contingent not only on its antidepressant-like effect but also on the essence and extent of its complications.

These studies highlight the potential of rutin for treating depression. Further research is necessary to elucidate the precise mechanisms of action and to establish a safe and tolerable dosing regimen. Additionally, exploration of potential side effects and interactions with other medications is crucial for responsible clinical development.

Kaempferol, a 3, 4, 5, 7-tetrahydroxyflavone, is a natural compound found in a variety of sources including tea, broccoli, tomatoes, Ginkgo biloba L., grapes, and other fruits and vegetables (Al-Ishaq et al., 2019). Preclinical studies suggest antidepressant potential for kaempferol. Reduced immobility time in animal models treated with kaempferol support this possibility (Park et al., 2010). Gao et al. (2019) further demonstrated kaempferol’s antidepressive-like effects in a chronic stress model, potentially mediated by enhanced anti-inflammatory and antioxidant actions via upregulation of AKT/β-catenin cascade activity. These findings are promising, but further investigation into kaempferol’s structure-activity relationships (SAR) is crucial to optimize its efficacy for depression treatment. Additionally, research is needed to elucidate the specific mechanisms of action and potential advantages of different kaempferol derivatives. In a study by Yan et al. (2015), kaempferol-3-O-D-glucoside, kaempferol, quercetin, and quercetin-3-O-D-glucoside were purified from the hydroethanolic extract of Apocynum venetum L. leaves. The behavioral test indicated amelioration of depressive-like symptoms in mice. The further biochemical assessment showed that anti-depressant activity could be dependent on the increase of main neurotransmitter levels including serotonin, dopamine, and norepinephrine as well as a reduction in the rate of serotonin metabolism. Future studies should also explore kaempferol’s safety and tolerability in humans and its potential interactions with other medications. Ultimately, clinical trials are necessary to confirm kaempferol’s efficacy in treating depression.

Kaempferitrin is a kaempferol dirhamnoside in which the hydroxyl groups at positions 3 and 7 are substituted. This compound is obtained from a variety of plants including the Justicia spicigera (Asteraceae) plant. Treatment with kaempferitrin is found to improve the performance of depressed mice in FST and TST. At the molecular level, kaempferitrin exerts its anti-depressant potential by modulating the activity of the serotonergic system, particularly through presynaptic 5-HT1A receptors and regulating hypothalamic-hypophysis-adrenal axis (HPA) (Cassani et al., 2014).

Icariin, also known as a prenylated flavonol glycoside, is an 8-prenyl derivative of kaempferol 3,7-O-glucoside. It is predominantly found in Herba epimedii, a traditional Chinese herb that has been used for centuries to treat various ailments (Pannu A. et al., 2021). Animal models demonstrate its ability to prevent social aversion and alleviate depressive symptoms through diverse mechanisms, including restoring hypothalamic-pituitary-adrenal (HPA) axis function, enhancing brain-derived neurotrophic factor (BDNF) levels, and reducing neuroinflammation and nitric oxide production (Wu et al., 2013; Liu et al., 2015). Additionally, studies have revealed that icariin and associated improvements in behavioral tests are accompanied by anti-inflammatory action, anti-oxidant action, Inhibited activation of NF-kB signaling, as well as a decrease in levels of SGK1 (serum and glucocorticoid-regulated kinase 1) and FKBP5 (FK506 binding protein 5) expression (Wei et al., 2016). Notably, Di et al. (2023) observed increased expression of monoamine neurotransmitters and BDNF-TrkB signaling pathway genes in mice treated with icariin, further supporting its potential antidepressant action (Di et al., 2023). While these findings are promising, investigations into SAR are essential to optimize icariin’s efficacy for depression treatment. Clinical trials are ultimately necessary to confirm its safety and efficacy in humans. Furthermore, icariin’s multi-target approach warrants further exploration to elucidate the relative contributions of each mechanism and potentially reveal advantages over traditional antidepressants.

Myricetin is a hexahydroxyflavone and is rich in fruits, vegetables, nuts, red wine, berries, and tea (Taheri et al., 2020). In a study by Ma et al. (2015) TST results showed that myricetin decreased immobility time. Biochemical assessments showed myricetin elevated the activities of glutathione peroxidase (GSH-PX) in the hippocampus of mice. In addition, it reduced plasma corticosterone levels of those mice to repeated restraint stress. In one study, it was shown that repeated treatment with myricitrin at 10 mg/kg resulted in increased mobility time in TST, which is possibly mediated by myricitrin-induced hippocampal neurogenesis and inhibition of nitric oxide (Meyer et al., 2017).

Preclinical studies suggest antidepressant potential for morin, a naturally occurring flavonoid. In a chronic stress model, morin treatment improved levels of key neurotransmitters (epinephrine, norepinephrine, and 5-HT) and reduced inflammatory markers including tumor necrosis factor-alpha, toll-like receptor-4, NOD-like receptor pyrin domain-containing protein-3, interleukin-1beta, and caspase-1 levels, as well as the status of the critical apoptotic marker, caspase-3 in the brain. These findings suggest its potential to alleviate depression through neurochemical and anti-inflammatory pathways (Hassan et al., 2020). However, Ben-Azu et al. (2019) observed that L-arginine, a substrate for nitric oxide synthesis, reversed morin’s antidepressant effects in mice. This suggests the involvement of the N(G)-nitro-l-arginine methyl ester is L-NAME in morin’s mechanism of action.

Quercetin is a pentahydroxyflavone and highly abundant in apples, onions, broccoli, wine, and plants such as green tea and Ginkgo biloba. Quercetin or its derivatives have been shown to alleviate depressive behaviors, potentially through various mechanisms including regulating neurotransmitter levels (Şahin et al., 2019; Samad et al., 2018; Yan et al., 2015), reducing oxidative stress (Şahin et al., 2019; Scheggi et al., 2016), microglia activation, and stress-induced apoptosis (Rinwa and Kumar 2013; Park et al., 2010). Additionally, the anti-depressant effect of quercetin is suggested to be possible via restoring serotonin levels and preventing brain oxidative stress by inhibiting MAO-A activity (Singh, Chauhan, and Shri, 2021) (Figure 4). Moreover, Hou et al. (2010) revealed that quercetin modulated depression-related signaling pathways involving BDNF and phosphorylation of cyclic adenosine monophosphate (AMP) response element-binding protein (CREB) and decreased amyloid-b peptide (Ab) in neurons isolated from double transgenic AD mouse. were reported.

Quercetin’s multifaceted effects on depression, potentially including memory enhancement, warrant further exploration to elucidate distinct mechanisms and potential advantages over traditional antidepressants.

Quercetin3-O- -D-glucoside is a type of quercetin O-glucoside. In this compound, quercetin is substituted with a -D-glucosyl residue at position C3. Among four flavonoids that were isolated from Apocynum venetum leaf, quercetin3-O-D-glucoside also showed anti-depressive activity with both gross changes (reduced immobility time) and biochemical alterations such as increased NE, DA, and 5-HT and reduced 5-HT metabolism (Yan et al., 2015).

Fisetin is a bioactive flavonoid found plentifully in vegetables and fruits, particularly in strawberries (Shukla et al., 2019). It demonstrates dose-dependent antidepressant effects in animal models, reducing immobility time and increasing serotonin and noradrenaline levels (Zhen et al., 2012). Fisetin’s potential mechanisms include anti-inflammatory activity, activation of the TrkB signaling pathway, and downregulation of the TNF-α/NLRP3 inflammasome (Yu et al., 2016; Wang et al., 2017; Gopnar et al., 2023). While fisetin demonstrates promise as a natural antidepressant, its synergistic potential with other natural compounds or traditional antidepressants warrants investigation. Exploring combinations could potentially enhance efficacy or address limitations associated with single-compound therapy.

Hyperoside, a natural flavonol, is commonly referred to as 3-O-galactoside of quercetin due to the presence of a β-D-galactosyl residue attached to C3. Multiple mechanisms have been proposed to explain its antidepressant effects. Haas et al. (2011) suggest hyperoside activates D2 dopamine receptors, potentially contributing to its efficacy. Additionally, studies by Zheng et al. (2012) and (Butterweck, Hegger, and Winterhoff 2004) indicate hyperoside may influence neurotrophic factors (BDNF, CREB) via the AC-cAMP-CREB pathway and regulate the hypothalamic-pituitary-adrenal (HPA), respetively. Recently, Song et al. (2022) reported the same symptom-relieving effect of hyperoside on CUMS challenged mice. Further assessment revealed that hyperoside could exert an anti-depressant effect by inhibiting the NLRP1 inflammasome through the CXCL1/CXCR2/BDNF signaling pathway. Compared to traditional antidepressants targeting specific neurotransmitters, hyperoside appears to act through multiple mechanisms, potentially offering a broader therapeutic approach for depression. Further research elucidating the relative contributions of each mechanism could reveal hyperoside’s potential for addressing different subtypes of depression or reducing side effects associated with single-target drugs.

Genistein is an isoflavonoid compound derived from soy that is known for its numerous health benefits (Setchell, Brown, and Lydeking-Olsen, 2002). It exhibits antidepressant-like effects through diverse mechanisms. Shen et al. (Shen et al., 2018) propose genistein downregulates miR-221/222, targeting connexin 43, a protein linked to depression. Furthermore, studies suggest genistein regulates monoamine metabolism, particularly serotonin, potentially explaining its antidepressant properties (Kageyama et al., 2010) (Figure 5).

Hu et al. (2017) observed a dose-dependent antidepressant effect in mice treated with genistein, accompanied by increased brain monoamines (noradrenaline, serotonin, and dopamine and their metabolites (5-HIAA and DOPAC)) and decreased monoamine oxidase activity. Another study investigated the acute and chronic antidepressant-like effects of 10 mg/kg of genistein in combination with 5 and 10 mg/kg of amitriptyline for 10 days on male albino mice. Notably, Gupta et al. (2015) demonstrated a synergistic effect when combining genistein with amitriptyline, suggesting potential benefits for treatment-resistant depressionAdditionally, a clinical study examining the effects of genistein consumption in postmenopausal women with osteopenia showed improved quality of life and alleviation of depression symptoms following the treatment (Atteritano et al., 2014). Genistein’s multi-target action, including microRNA modulation and neurotransmitter regulation, warrants further exploration to elucidate its potential advantages over traditional antidepressants, particularly in treatment-resistant cases and combination therapies.

Daidzein, an isoflavone commonly found in soy, can be converted into equol, a compound with higher estrogenic potency than other isoflavones (Setchell, Brown, and Lydeking-Olsen, 2002). Chen et al. (2021) showed that daidzein effectively reversed the inescapable shock-induced helplessness behavior in a group of learned helplessness rats, and the immobility time in CUMS challenged mice via mitigating HPA axis hyperactivity, and partially correcting the imbalances in inflammatory cytokines.

Apigenin is one of the most widespread flavones in grapefruits, oranges, celery, and onions. It demonstrates antidepressant-like effects through diverse mechanisms. Antidepressant outcome of apigenin might be related to the inhibition of pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), inducible Nitric Oxide Synthase (iNOS), and cyclooxygenase-2 (COX-2) utterance in the brain (Li et al., 2015). Furthermore, apigenin appears to modulate neurotransmitter levels (dopamine, serotonin) (Nakazawa et al., 2003; Yi et al., 2008), and increase BDNF (Weng et al., 2016).

Additionally, 20 mg/kg apigenin for 3 weeks in male mice treated with CUMS caused a decrease in the levels of provocative brain cytokines (IL-18 and IL-1β), changes in oxidative stress parameters (reducing malondialdehyde (MDA) levels, and restoring the reduced glutathione (GSH) levels), and a decrease in expression of NLRP3 inflammatory activation (Li et al., 2016b). Moreover, apigenin treatment was found to exert anti-depressive effects by increasing the level of hippocampal microtubule-associated protein light chain 3-II/I (LC 3-II/I) while decreasing p62 expression, the levels of adenosine monophosphate-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase-1 (ULK1). It also inhibited the levels of mTOR. overall indicating that apigenin potentially increased autophagy through the AMPK/mTOR pathway (Zhang et al., 2019) (Figure 4). Apigenin’s multifaceted approach, targeting inflammation, neurotransmitters, BDNF, and autophagy, suggests potential advantages over traditional antidepressants with more limited mechanisms of action. Further research is warranted to elucidate the relative contributions of each mechanism and explore apigenin’s efficacy in human trials.

Baicalein demonstrates diverse mechanisms underlying its antidepressant-like effects. Studies suggest baicalein activates the ERK and BDNF pathways in the hippocampus, potentially promoting neurotrophic activity (Xiong et al., 2011). Additionally, it appears to alleviate neuroinflammation by inhibiting the NF-κB pathway (Du et al., 2019), restore dopamine levels and increase BDNF expression (Lee et al., 2013), and even enhance hippocampal neurogenesis through the cAMP/PKA pathway (Zhang et al., 2018). The superior potency of Baicalein compared to other flavones warrants further investigation. This suggests Baicalein’s potential as a lead compound for antidepressant development due to its multi-targeted mechanisms and potentially broader spectrum of action.

The flavone chrysin is contained in various plants and is also found in propolis and honey, and many studies have shown its antidepressant-like effects (Rao et al., 2016; Rodríguez-Landa et al., 2022). It can also affect different brain parts, such as the prefrontal cortex, hippocampus, and raphe nucleus (Rodríguez-Landa et al., 2022). It can activate neurological factors, regulate biomarkers of oxidative stress, and regulate the apoptotic signaling pathway, which causes the antidepressant-like effects of this flavonoid (Rodríguez-Landa et al., 2022).

Several studies have shed light on the diverse mechanisms underlying chrysin’s antidepressant potential. One mechanism involves modulation of the serotonergic system.German-Ponciano et al. (2021) demonstrated that chronic administration of chrysin in rats influenced the expression of 5-HT receptor subtypes in brain regions associated with mood, suggesting its ability to regulate serotonin signaling. Furthermore, chrysin appears to positively influence the production of neurotrophic factors like BDNF and NGF (Jesse et al., 2015). These neurotrophic factors play a crucial role in neuronal growth, survival, and differentiation, and their downregulation is implicated in depression. By promoting neurotrophic factor production, chrysin may contribute to neurogenesis and neuronal resilience, potentially reversing depressive symptoms.

Another promising aspect of chrysin’s antidepressant potential lies in its antioxidant and anti-inflammatory properties. Studies by Borges Filho et al. have shown that chrysin can counteract oxidative stress and inflammation (Borges Filho et al., 2016a). By mitigating these detrimental processes, chrysin may offer neuroprotective effects and alleviate depressive symptoms associated with neuroinflammation.

Chrysin’s interaction with the GABAergic system, another critical pathway involved in mood regulation, presents a further avenue for investigation. Cueto-Escobedo et al. (2020) observed that chrysin’s antidepressant-like effects were blocked by an antagonist of the GABAergic system, suggesting its potential role in modulating GABAergic neurotransmission (Cueto-Escobedo et al., 2020). Further research is necessary to elucidate the precise mechanisms by which chrysin interacts with this system.

Additionally, German-Ponciano et al. (Germán-Ponciano et al., 2020), compared the results of a single injection and 21 consecutive days of treatment with chrysin 2, 4, and 8 μmol kg⁻¹ on anxiety-like behavior in male Wistar rats. The authors compared the effects of chrysin with anxiolytic diazepam 7 μmol kg⁻¹. They indicated that diazepam had similar effects as acute (not chronic) treatment, with 4 μmol kg⁻¹ chrysin exerting anxiolytic- and anti-depressant-like effects.

The multifaceted mechanisms of chrysin, targeting the serotonergic system, neurotrophic factors, inflammation, and the GABAergic system, suggest potential advantages over traditional antidepressants with more limited mechanisms of action (Borges Filho et al., 2016b). Further research is warranted to elucidate the relative contributions of each mechanism and explore chrysin’s efficacy in human trials. If successful, chrysin could offer a novel therapeutic approach for treating depression with a broader spectrum of action and potentially fewer side effects.

Luteolin is a 30, 40 5, 7, tetrahydroxyflavone natural flavonoid and also found to easily cross BBB. Luteolin administration in rats exposed to single prolonged stress who developed depressive-like behavior has resulted in alleviated depression- and anxiety-like behaviors and reversed the elevated plasma corticosterone and adrenocorticotropic hormone levels. These changes were accompanied by a decrease in norepinephrine and an increase in serotonin levels in the prefrontal cortex and hippocampus. Therefore, the anti-depressant properties of luteolin could be due to its role in correcting the HPA axis dysregulation (Sur and Lee, 2022). similarly Cheng et al. (2022) demonstrated that luteolin’s anti-depressant activity could be attributed to the reversal of neuroinflammation. In this study, luteolin treatment not only effectively reduced inflammation in the hippocampus and prefrontal cortex but also enhanced synapsin levels. Also, a significant increase in the levels of serum 5-hydroxytryptamine and norepinephrine was observed in the treatment group. Several other studies also provided evidence of luteolin’s function as an anti-depressant agent (Ishisaka et al., 2011; de la Peña et al., 2014). Luteolin’s multifaceted approach, targeting stress hormones, neuroinflammation, synaptogenesis, and monoamine neurotransmitters, suggests potential advantages over traditional antidepressants.

Nobiletin is a safe and non-toxic flavonoid compound extracted from citrus peel. It belongs to the group of polymethoxylated flavonoids (Alam et al., 2022). According to Wang et al. (2020) nobiletin administration in rats exposed to LPS has been found to improve the behavioral patterns related to depression. The molecular assessment confirmed that nobiletin reversed the neuroinflammation caused by LPS, promoted autophagy, and suppressed the activation of NLRP3 inflammasome possibly via the AMPK pathway. In another study, nobiletin was also found to attenuate depressive behavior according to TST and FST results. In this study, the anti-depressant potential of nobiletin was ascribed to its interaction with noradrenergic, serotonergic, and dopaminergic systems (Yi et al., 2011).

7,8-dihydroxyflavone is a natural flavone that has demonstrated antidepressant effects in various studies. This flavonoid can penetrate the blood-brain barrier and is suitable for oral consumption, making it capable of interacting with critical pathways involved in depression in the brain (Yang and Zhu, 2022). The antidepressant effects of 7,8-dihydroxyflavone are primarily reported to be associated with increased expression of BDNF. Two studies have shown that chronic administration of 7,8-dihydroxyflavone improves depression-like behaviors in rats by acting as an agonist on the TrkB receptor, which subsequently increases hippocampal expression of BDNF (Zhang et al., 2014; Zhang et al., 2016). In addition, an additive effect of 7,8-dihydroxyflavone on conventional depression treatments, such as fluoxetine, has been observed to improve behavioral performance tests (Amin et al., 2020). This effect was associated with the upregulation of autophagy (a process that maintains energy homeostasis) through increased activation of the PI3/Akt/mTOR/ERK signaling pathway.

Amentoflavone is a biflavonoid compound consisting of a dimer of apigenin at position C8. It possesses a range of pharmacological properties, including neuroprotective, antioxidative, and anti-inflammatory effects (Yu et al., 2017). Additionally, there is evidence to suggest that it can cross the blood-brain barrier. In a preclinical study, Ishola et al. (2012) found that amentoflavone displayed anxiolytic and antidepressant effects in mice mediated by interactions with 5-HT2 receptors, α1-and α2-adrenoceptors, while the anxiolytic effect appears to involve the GABAergic system. Overall, these findings suggest that amentoflavone may exert antidepressant effects by modifying neurotransmitters and their receptors.

Hesperidin (4′-methoxy-7-O-rutinosyl-3′,5-dihydroxyflavanone) is a natural bioflavonoid primarily found in citrus fruits such as fingered citron (Garg et al., 2001).

Multiple studies have shed light on the diverse mechanisms underlying hesperidin’s antidepressant potential. One mechanism involves modulating inflammatory pathways. Fu et al. (2019) demonstrated that hesperidin treatment in mice exposed to chronic unpredictable stress reduced levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). This anti-inflammatory effect appears to be mediated by the attenuation of the BDNF/TrkB and high-mobility–group box; chromosomal protein 1 (HMGB1)/receptor for advanced glycation end-product (RAGE)/NF-κB signaling pathways, both of which are implicated in depression. Furthermore, hesperidin appears to promote neurotrophic activity by increasing BDNF expression through various mechanisms (Donato et al., 2014; Li et al., 2016a).

In another study, Donato et al. (2015) also showed that hesperidin could play its antidepressant role by the inhibition of K+ channels, leading to the inhibition of the L-NAME pathway in male mice.

Hesperidin’s influence extends to neurotransmitter systems. Studies suggest it may modulate serotonin and dopamine levels in the brain (Souza et al., 2013; Nadar et al., 2018). Hesperidin’s ability to influence these neurotransmitters suggests a potential avenue for its therapeutic effects. Additionally, hesperidin exhibits antioxidant properties. A study by Filho et al. (2013) indicated that hesperidin could play its antidepressant role in the FST by the interaction with the k-opioid receptors in male mice. Diabetic male rat models treated with had enhanced Glo-1, an enzyme that detoxifies alpha-carbonyl aldehydes. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is known to be responsible for this change. Therefore, administering hesperidin might play an antidepressant-like role in diabetic rats (Zhu et al., 2020). Animal models of posttraumatic stress disorder (PTSD) treated with hesperidin (20, 50, and 100 mg/kg) for 14 days had a decreased 5-HIAA/5-HT ratio (Lee Bombi et al., 2020). Postartum depression mouse models treated with hesperidin (0.1, 0.5, and 1 mg/kg) showed decreased immobility time in TST and FST in postpartum mice. Molecular examination revealed a decrease in MDA levels after hesperidin treatment, suggesting an antioxidative mechanism that may contribute to the compound’s potential antidepressant effects. The results show that treatment with hesperidin can be effective (Khodadadeh, Hassanpour, and Akbari, 2020). Several additional studies have demonstrated the alleviation of depressive behavior in animal models of depression treated with hesperidin. These studies proposed various mechanisms underlying its effects, including increased neurogenesis and BDNF levels, increased ERK phosphorylation (Li et al., 2016a), modulation of pro-inflammatory cytokines (Antunes et al., 2016; Xie et al., 2020), suppression of microglia activation (Xie et al., 2020), and inhibition of acetylcholinesterase activity (Antunes et al., 2016). Hesperidin’s multifaceted approach, targeting inflammation, neurotrophic factors, neurotransmitters, and oxidative stress, suggests potential advantages over traditional antidepressants with more limited mechanisms of action.

Naringenin, a trihydroxyflavanone, is abundant in the peel of citrus fruits (Amin N. et al., 2020).

Multiple studies have shed light on the diverse mechanisms underlying naringenin’s antidepressant potential. One mechanism involves modulating the kynurenine pathway, a metabolic pathway of the amino acid tryptophan. Dysregulation of this pathway, leading to increased production of neurotoxic metabolites, is implicated in depression (Bansal et al., 2018). Naringenin treatment in animal models has been shown to restore imbalances in the kynurenine pathway, potentially mitigating its detrimental effects. Furthermore, naringenin exhibits anti-inflammatory properties, reducing levels of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β (Bansal et al., 2018). Chronic inflammation is increasingly recognized as a contributing factor in depression, and naringenin’s ability to counteract this process may contribute to its therapeutic effects.

Naringenin’s influence extends beyond inflammation and neurotransmitter modulation. Studies suggest it may activate the Sonic Hedgehog (SHH) signaling pathway (Tayyab et al., 2019). In animal models of depression, naringenin treatment has been shown to upregulate BDNF, SHH, GLI1, NK2 Homeobox 2 (NKX2.2), and Paired box protein Pax-6 (PAX6). Additionally, naringenin appears to enhance serotonergic and noradrenergic systems by increasing levels of serotonin, norepinephrine, and glucocorticoid receptors in the hippocampus (Yi et al., 2010). These neurotransmitters play a key role in mood regulation, and their dysregulation is associated with depression. Naringenin’s ability to influence these systems suggests a potential mechanism for its antidepressant effects.

Investigating the underlying mechanisms involved in the anti-depressant properties of naringenin revealed the involvement of the BDNF signaling pathway. Naringenin was found to increase the expression of BDNF in the hippocampus of depressed rats in several studies, resulting in improved outcomes of behavioral tests (Yi et al., 2014; Zhang et al., 2023; Olugbemide et al., 2021). Several studies have also highlighted naringenin’s antioxidant and anti-inflammatory properties (She et al., 2021). For instance, studies have shown that naringenin treatment reduces oxidative damage, decreases the expression of the pro-inflammatory NF-κB protein, and shifts the microglia population towards the anti-inflammatory M2 phenotype (Zhang et al., 2023). These findings suggest that naringenin may target multiple aspects of the neuroinflammatory response, potentially contributing to its antidepressant effects.

Naringin, a flavanone-7-O-glycoside compound consisting of 40-hydroxyflavanones, is naturally present in citrus fruits, with grapes exhibiting significantly higher concentrations. This organic compound is responsible for the bitter taste of fruits (Suseem and Dhanish, 2019). Naringin exhibits a surprising benefit–antidepressant- and anxiolytic-like effects in mice. Behavioral improvements across various tests, such as reduced immobility time and increased social interaction preference, suggest naringin’s potential therapeutic value (Ben-Azu et al., 2018).

Studies suggest naringin exerts neuroprotective effects by reducing oxidative stress and improving mitochondrial function in models of post-stroke depression (Aggarwal, Gaur, and Kumar 2010). Oxidative stress is increasingly recognized as a contributing factor in depression, and naringin’s ability to mitigate these detrimental processes may offer neuroprotective benefits and alleviate depressive symptoms associated with neuroinflammation. Furthermore, naringin appears to target specific signaling pathways in the hippocampus. Studies have shown that naringin can inhibit NMDA receptors, potentially regulating neuronal excitability, and promote neurogenesis via activation of the cAMP response element-binding protein (CREB) signaling pathway, which plays a crucial role in the growth and survival of new neurons (Wang et al., 2023; Gao et al., 2022). These findings suggest naringin may promote neuroplasticity, the brain’s ability to adapt and form new connections, potentially offering a long-term therapeutic benefit for depression.

Naringin’s influence may extend beyond neuroprotection and neurogenesis. Studies suggest it may modulate neurotransmitter systems by normalizing the activity of the enzyme AchE, thereby potentially influencing levels of the neurotransmitter acetylcholine (Oladapo et al., 2021). Additionally, naringin appears to promote GABAergic neurotransmission, potentially and reducing neuroinflammation as well as oxidative stress. Similarly, Kwatra et al. (2016) reported the same reduction in the levels of pro-inflammatory cytokines as well as a decrease in the previously elevated serum corticosterone. The authors also examined the synergistic effect of naringenin with sertraline in mice with depression and discovered that the combination of these two substances alleviated depressive-like behavior through the regulation of the 5-HT level and protection of the mitochondrial complexes pathway, as well as by reducing oxidative stress in the hippocampus. These findings suggest naringin may exert its antidepressant effects through a multifaceted approach, targeting multiple neurotransmitter systems. Moreover, naringin exhibits anti-inflammatory properties, as evidenced by reduced levels of pro-inflammatory cytokines. Chronic inflammation is increasingly recognized as a contributing factor in depression, and naringin’s ability to counteract this process may contribute to its therapeutic effects.

Eriodictyol is a flavanone widely abundant in medicinal plants, citrus fruits, and an array of vegetables (Islam et al., 2020). Zhang et al. (2020) assessed the antidepressant-like effects of chronic eriodictyol (10, 30, and 100 mg/kg) in male rat models of depression. The authors reported that 100 mg/kg eriodictyol for 28 days had antidepressant-like effects and improved cognitive impairments induced by chronic stress in rats. In another study on a group of depressive middle-aged Korean females showed that they had lower flavonoid intake, including eriodictyol (Park, Jaiswal, and Lee, 2021).