Figure 3.

Possible mechanisms of action involved in the antidepressant-like effect of chrysin. (A) The flavonoid chrysin can modulate ERα and ERβ of membrane, which triggers the MAPK/ERK1/2 signaling pathway involved in phosphorylation and subsequent CREB activation ($\uparrow$CREB), which promotes the increase of BDNF levels ($\uparrow$BDNF) [11,19,20,43], which can further activate the MAPK/ERK1/2 signaling by the TrkB interaction [56]. The above-mentioned pathway also promotes an increase of TpOH expression ($\uparrow$TpOH) and serotonin levels ($\uparrow$Serotonin) resulting in the antidepressant-like effect [12,25]. (B) Furthermore, chrysin can decrease the pro-inflammatory cytokine levels ($\downarrow$TNF-α, $\downarrow$IL-1β, $\downarrow$IL-6, $\downarrow$IFN-γ), which inhibits IDO activity ($\downarrow$IDO) improving serotonergic neurotransmission and producing its antidepressant-like effect [25]. ER = estrogen receptor; MAPK = mitogen-activated-protein-kinases; CREB = cAMP response element binding; BDNF = brain derived neurotrophic factor; TrkB = tropomyosinreceptor kinase B; TpOH = tryptophan-hydroxylase; TNF-α = tumor necrosis factor-α; IL-1β = interleukin 1 beta; IL-6 = interleukin 6; IFN-γ = interferon gamma; IDO = indoleamine 2,3-dioxygenase; ERK1/2 = extracellular signal-regulated kinase 1 and 2; KYN = kynurenine. (Figure was prepared by the authors).