Participation of the Serotonergic System and Brain-Derived Neurotrophic Factor in the Antidepressant-like Effect of Flavonoids

Abstract

Depressive disorders are among the most disabling diseases experienced around the world, and their incidence has significantly increased over the last few decades due to multiple environmental, social, and biological factors. The search for new pharmacological alternatives to treat depression is a global priority. In preclinical research, molecules obtained from plants, such as flavonoids, have shown promising antidepressant-like properties through several mechanisms of action that have not been fully elucidated, including crossing of the blood brain barrier (BBB). This review will focus on discussing the main findings related to the participation of the serotonergic system and brain-derived neurotrophic factor (BDNF) on the antidepressant-like effect of some flavonoids reported by behavioral, neurochemical, and molecular studies. In this sense, evidence shows that depressive individuals have low levels of serotonin and BDNF, while flavonoids can reverse it. Finally, the elucidation of the mechanism used by flavonoids to modulate serotonin and BDNF will contribute to our understanding of the neurobiological bases underlying the antidepressant-like effects produced by these natural compounds.

Keywords: BDNF; depression; flavonoid; polyphenol; serotonin.

Figure 1

Possible implication of serotonergic system and BDNF in the antidepressant-like effect of flavonoids. Long-term treatment with flavonoids decreases the expression of presynaptic (raphe nucleus) 5-HT_1A (a) and 5-HT_2A (b) receptors and can also increase the expression of TpH-1 (c), both of which improve the 5-HT levels (d) in several postsynaptic areas (i.e., HP, PFC, HYP, and AMY), increasing the levels of postsynaptic 5-HT_1A receptors (e). The high levels of 5-HT promote CREB expression (f), which stimulates the increase in mRNA (g) and protein (h) of TrkB receptor. Similarly, the levels of mRNA (i) and protein (j) of BDNF are increased. The above improves the neuroplasticity, neuronal survival, and neurogenesis, which is reflected in the appearance of the antidepressant-like effect of flavonoids. 5-HT_1A = serotonin 1A receptor; 5-HT_2A = serotonin 2A receptor; Tph-1 = tryptophan hydroxylase 1; 5-HT = serotonin; HP = hippocampus; PFC = prefrontal cortex; HYP = hypothalamus; AMY = amygdala; CREB = cAMP response element-binding; mRNA = messenger ribonucleic acid; TrkB = tropomyosin receptor kinase B; BDNF = brain-derived neurotrophic factor.