TABLE 1.

A summary of possible cellular and molecular mechanisms of anti-depressant action of flavonoids.

Chalcones	DHIPC	1. Increased the concentrations of the main neurotransmitters serotonin and noradrenaline in the brain (Zhao et al., 2018) 2. Increased 5-hydroxyindoleacetic acid contents in the hippocampus (Zhao et al., 2018)
	Phlioridzin	1. Enhancing the expression of GSH, BDNF, TrkB, CREB, and ERK (Kamdi, Raval, and Nakhate, 2021)
Anthocyanins	Cyanidin	1. Inhibition of monoamine oxidases activity (Fang et al., 2020) 2. Increased production of BDNF (Fang et al., 2020; Qu et al., 2022) 3. Upregulation of the PI3K/AKT/FoxG1/FGF-2 pathway (Shan et al., 2020) 4. Decrease the production of pro-inflammatory cytokines (Qu et al., 2022) 5. Upregulation of GFAP, GLAST, EAAT2 (Qu et al., 2022)
	Delphinidin	1. Inhibiting oxidative stress (Di Lorenzo et al., 2019)
	Malvidin	1. Maintaining synaptic plasticity by increasing Rac1 expression (Wang et al., 2018)
Flavonols	Rutin	1. Increasing the access of noradrenaline and serotonin in the synaptic cleft (46) 2. Protecting from oxidative stress (Scheggi et al., 2016)
	Kaempferol	1. Enhancement of anti-inflammation effects and antioxidant abilities via upregulation of AKT/β-catenin cascade activity (Gao et al., 2019) 2. Increase of NE, DA, and 5-HT (Yan et al., 2015) 3. Increase of POMC mRNA or plasma β-endorphin level (Park et al., 2010)
	Kaempferol-3-O-_-Dglucose	1. Increase of NE, DA and 5-HT (Yan et al., 2015)
	Kaempferitrin	1. Regulating serotonergic system via interaction with presynaptic 5-HT1A receptors (Cassani et al., 2014) 2. Regulating HPA axis (Cassani et al., 2014)
	Myricetin	1. Improving the activities of glutathione peroxidase (GSH-PX) in the hippocampus (Ma et al., 2015) 2. Reducing plasma corticosterone levels (Ma et al., 2015) 3. Normalize BDNF levels in the hippocampus (Ma et al., 2015)
	Myricitrin	1. Inhibition of nitric oxide (Meyer et al., 2017) 2. Promoting hippocampal neurogenesis (Meyer et al., 2017)
	Morin	1. Probability of influencing the role of the L-arginine-nitric oxide pathway (Ben-Azu et al., 2019) 2. Elevating the epinephrine, norepinephrine, and serotonin levels in both the hippocampus and the cortex (Hassan et al., 2020) 3. Decreasing the tissue levels of inflammatory markers; TNF-alpha, TLR-4, NLRP3, IL-1beta, caspase-1 and caspase-3 levels (Hassan et al., 2020)
	Quercetin	1. Modulation of inflammation (Şahin et al., 2019) 2. Regulating the serotonergic enzymes (Singh, Chauhan, and Shri, 2021; Samad et al., 2018) 3. Preventing brain oxidative stress by inhibiting MAO-A activity (Şahin et al., 2019; Samad et al., 2018; Singh, Chauhan, and Shri, 2021; Scheggi et al., 2016) 4. Producing cholinergic neurotransmissions (Samad et al., 2018) 5. Increasing the expression of BDNF (Hou et al., 2010) 6. Suppressing oxidative/nitrosative stress-mediated neuroinflammation/apoptotic cascade (Rinwa and Kumar 2013) 7. Increase of NE, DA, and 5-HT (Yan et al., 2015) 8. Neuroprotective effects via microglial inhibitory pathway (Rinwa and Kumar 2013)
	Quercetin3-O-D-glucoside	1. Increase of NE, DA and 5-HT (4)
	Icariin	1. Anti-oxidant action (Liu et al., 2015) 2. Inhibiting NF-kB signaling (Liu et al., 2015) 3. Inhibiting NLRP3 -inflammasome/caspase-1/IL-1b axis (Liu et al., 2015) 4. Increasing BDNF expression (Wu et al., 2013; Di et al., 2023; Gong et al., 2016) 5. Inhibiting the production of inflammatory cytokines 6. (TNF-alpha, IL-6, IL-1β) (Wu et al., 2013; Liu et al., 2015; Di et al., 2023) 7. Restoring the glucocorticoid sensitivity (Wu et al., 2013) 8. Regulation of the HPA- axis (Wei et al., 2016) 9. Lowering the expression levels of FKBP5 and SGK1 (Wei et al., 2016) 10. creasing the expression of monoamine neurotransmitters such as 5-HT, dopamine, and norepinephrine (Di et al., 2023) 11. upregulating the relative expression levels of p-TrkB/TrkB, p-Akt/Akt, p-CREB/CREB, MAPK3, MAPK1, Bcl-2, EGFR, and mTOR (Di et al., 2023)
	Hyperoside	1. Activation of D2-DA receptors of the dopaminergic pathway (Haas et al., 2011) 2. inhibiting the NLRP1 inflammasome via CXCL1/CXCR2/BDNF signaling pathway (Song et al., 2022) 3. including increased expression of BDNF and CREB (Zheng et al., 2012) 4. up-regulating the AC–cAMP–CREB signaling pathway (Zheng et al., 2012) 5. Decreasing plasma ACTH and corticosterone concentration (regulation of HPA axis) (Butterweck, Hegger, and Winterhoff, 2004)
	Fisetin	1. Regulation of central serotonin and noradrenaline levels (Zhen et al., 2012) 2. Reversing the overexpression of proinflammatory cytokine (especially, IL-6, IL-1, and TNF-α) (Yu et al., 2016) 3. NF-kB modulation (Yu et al., 2016) 4. Activating the TrkB signaling pathway (Wang et al., 2017) 5. Downregulation of TNF-α/NLRP3 expression (Gopnar et al., 2023)
Isoflavonoids Flavanones	Genistein	1. Down-regulating miR-221/222 (a microRNA that increases in the prefrontal cortex of depressed patients) by targeting connexin 43 (Shen et al., 2018) 2. Regulating the serotonergic enzymes (Hu et al., 2017; Kageyama et al., 2010)
	Daidzein	1. Decrease of stress-related hormones (Chen et al., 2021) 2. Mitigating HPA axis hyperactivity (Chen et al., 2021) 3. Decrease of inflammatory cytokines (Chen et al., 2021)
	Apigenin	1. Inhibition of inflammatory cytokines, iNOS, and COX-2 in the brain (Li et al., 2015; Li et al., 2016b) 2. Regulating dopaminergic mechanisms and their effect on DOPAC, DA, and HVA concentrations in the mice brain (Nakazawa et al., 2003) 3. Increased serum corticosterone and reduction in the level of hippocampal BDNF (Weng et al., 2016) 4. Regulating the serotonergic enzymes (Yi et al., 2008) 5. Increasing autophagy through the AMPK/mTOR pathway (Zhang et al., 2019)
	Baicalein	1. Reversing the reduction of extracellular ERK phosphorylation (Xiong et al., 2011) 2. Enhancing level of hippocampal BDNF expression (Xiong et al., 2011) 3. Promoting hippocampus neurogenesis via upregulating cAMP/PKA pathway (Zhang et al., 2018) 4. Ameliorating neuroinflammation (Du et al., 2019)
	Chrysin	5. Enhancing level of hippocampal BDNF expression (Jesse et al., 2015; Borges Filho et al., 2016a) 6. Increasing Na+,K + -ATPase activity (Jesse et al., 2015) 7. Decreasing ACTH and corticosterone levels (Borges Filho et al., 2016b; Jesse et al., 2015) 8. Inhibiting the production of inflammatory cytokines 9. (TNF-alpha, IL-6, IL-1β) (Borges Filho et al., 2016a; Borges Filho et al., 2016b) 10. Lowering 5-HT1A and 5-HT2A receptors in raphe nucleus and increasing hippocampal 5-HT1A and 5-HT2A (German-Ponciano et al., 2021) 11. interaction with GABAA receptors (Cueto-Escobedo et al., 2020)
	Luteolin	12. Lowering plasma corticosterone and adrenocorticotropic hormone levels (Sur and Lee, 2022) 13. Inhibiting the MAO enzyme, decreasing norepinephrine, and increasing serotonin levels in prefrontal cortex and hippocampus (Sur and Lee, 2022; Cheng et al., 2022; de la Peña et al., 2014) 14. Enhancing synapsin levels (Cheng et al., 2022) 15. Inhibiting inflammation in the hippocampus (Cheng et al., 2022) 16. Suppression of hippocampal expression of stress-related protein of endoplasmic reticulum (Ishisaka et al., 2011) 17. Potentiation of GABA-A receptor-calcium ion channels (de la Peña et al., 2014) 18
	Nobiletin	19. Reversing neuroinflammation (Wang et al., 2020) 20. Promoting autophagy (Wang et al., 2020) 21. Suppressing the activation of NLRP3 inflammasome possibly via the AMPK pathway (Wang et al., 2020) 22. Interaction with noradrenergic, serotonergic, and dopaminergic systems (Yi et al., 2011)
	7,8-Dihydroxyflavone	23. Elevating the expression of BDNF (Zhang et al., 2014) 24. Modulation of nitric oxide signaling pathway (Zhang et al., 2014) 25. Acting as TrkB receptor-specific agonist (Zhang et al., 2016)
	Amentoflavone	1. Interactions with 5-HT2 receptors, α1- and α2-adrenoceptors
Flavanones	Hesperidin	1. Reducing inflammatory cytokine levels (Fu et al., 2019; Antunes et al., 2016; Xie et al., 2020) 2. Suppressing microglia activation (Xie et al., 2020) 3. Inhibiting the l-arginine-NO-cGMP pathway (Donato et al., 2014) 4. Increasing hippocampal BDNF levels (Donato et al., 2014; Antunes et al., 2016; Li et al., 2016a) 5. Inhibition of K+ channels, leading to the inhibition of L-NAME pathway (Donato et al., 2015) 6. Interaction with the k-opioid receptors (Filho et al., 2013) 7. Involvement of serotonergic 5-HT1A receptors (Souza et al., 2013) 8. Activation of the Nrf2/ARE pathway (Zhu et al., 2020) 9. Maintaining brain plasticity (Antunes et al., 2016) 10. Inhibition of acetylcholinesterase activity (Antunes et al., 2016) 11. Increasing ERK phosphorylation (Li, Chen, et al., 2016)
	Naringenin	1. Restoring changes in the kynurenine pathway, the product of tryptophan catabolism as a result of oxido-inflammatory stress (Bansal et al., 2018) 2. Upregulating of SHH, GLI1, NKX2.2, and Paired box protein Pax-6 (PAX6) (Tayyab et al., 2019) 3. Increasing the expression of BDNF in the hippocampus (Tayyab et al., 2019; Yi et al., 2014; Bansal et al., 2018; Zhang et al., 2023; Olugbemide et al., 2021) 4. Inhibiting the production of inflammatory cytokines 5. (TNF-alpha, IL-6, IL-1β) (Bansal et al., 2018; Olugbemide et al., 2021) 6. NF-kB modulation (Bansal et al., 2018; Olugbemide et al., 2021) 7. suppressing microglia activation (Zhang et al., 2023) 8. Involvement of serotonergic and noradrenergic systems (Yi et al., 2010; Yi et al., 2012; Zhang et al., 2023) 9. Anti-oxidative activity (She et al., 2021)
	Naringin	1. Reduction of oxidative damage and regulation of mitochondrial enzyme complex activities (Aggarwal, Gaur, and Kumar 2010) 2. Lowering plasma corticosterone (Kwatra et al., 2016) 3. Modulation of 5-HT1A and kappa-opioid receptors (Kwatra et al., 2016) 4. Inhibiting NMDA receptors in the hippocampus (Wang et al., 2023) 5. Activation of PKA/CREB/BDNF pathway (Wang et al., 2023) 6. Neurogenesis by activating CREB signaling (Gao et al., 2022) 7. Increasing the levels of GAD67 and inhibiting AChE activities (Oladapo et al., 2021) 8. Anti-oxidative activity (Oladapo et al., 2021) 9. Inhibiting the production of inflammatory cytokines (TNF-alpha, IL-6, IL-1β) (Kwatra et al., 2016; Oladapo et al., 2021)