Phytochemicals Modulate Biosynthesis and Function of Serotonin, Dopamine, and Norepinephrine for Treatment of Monoamine Neurotransmission-Related Psychiatric Diseases

Abstract

Serotonin (5-HT), dopamine (DA), and norepinephrine (NE) are key monoamine neurotransmitters regulating behaviors, mood, and cognition. 5-HT affects early brain development, and its dysfunction induces brain vulnerability to stress, raising the risk of depression, anxiety, and autism in adulthood. These neurotransmitters are synthesized from tryptophan and tyrosine via hydroxylation and decarboxylation, and are metabolized by monoamine oxidase (MAO). This review aims to summarize the current findings on the role of dietary phytochemicals in modulating monoamine neurotransmitter biosynthesis, metabolism, and function, with an emphasis on their potential therapeutic applications in neuropsychiatric disorders. Phytochemicals exert antioxidant, neurotrophic, and neurohormonal activities, regulate gene expression, and induce epigenetic modifications. Phytoestrogens activate the estrogen receptors or estrogen-responsive elements of the promoter of target genes, enhance transcription of tryptophan hydroxylase and tyrosine hydroxylase, while inhibiting that of MAO. These compounds also influence the interaction between genetic and environmental factors, potentially reversing dysregulated neurotransmission and the brain architecture associated with neuropsychiatric conditions. Despite promising preclinical findings, clinical applications of phytochemicals remain challenging. Advances in nanotechnology and targeted delivery systems offer potential solutions to enhance clinical efficacy. This review discusses mechanisms, challenges, and strategies, underscoring the need for further research to advance phytochemical-based interventions for neuropsychiatric diseases.

Keywords: catecholamines; monoamine oxidase; neuropsychiatric diseases; neurotransmission; phytochemicals; serotonin; tryptophan hydroxylase; tyrosine hydroxylase.

Figure 1

Biosynthesis and metabolism of 5-HT. TPH hydroxylates L-tryptophan to 5-hydroxytryptophan (5-HTP), which AADC decarboxylates to 5-HT. MAO-A oxidizes 5-HT to its aldehyde, which ALDH oxidizes to 5-hydroxyindolacetic acid (5-HIAA). TPH requires BH₄ and O₂ for hydroxylation (H₂O) and quinonoid dihydrobiopterin (q-BH₂).

Figure 2

Biosynthesis pathway of catecholamine neurotransmitters in the brain. TH hydroxylates L-tyrosine to L-DOPA, which AADC decarboxylates to DA. DBH hydroxylates DA into NE, which is methylated to E by PNMT. DA are oxidized by MAO-A and MAO-B to the corresponding aldehydes and further oxidized by ALDH and O-methylates by COMT.

Figure 3

Classification and chemical structures of major phytochemicals discussed in the text.

Figure 4

Structures required for antioxidant actions of flavonoids. (I); for radical scavenging (II); for metal chelating. The catechol group (3′, 4′-hydroxyl group) in the ring B, 2,3-double bond in conjugation with a 4-keto function in ring C and 3- and 5-hydroxyl group in rings C and A are essential structures for antioxidant function.

Figure 5

Estrogen binds to ERβ, forming a complex that activates ERE at the TPH2 or TH promoter, or binds to Sp1, AP-1, CCAAT/enhancer binding protein b (C/EBPβ), or NF-κB, then to their binding sites, promotes the expression. Estrogen binds to GPER1, activates protein kinases cascade and transcription factors. Estrogen binds ERE and downregulates MAO-A transcription. Sex-determining region also regulates MAO-A transcription. Stress increased glucocorticoid and activated MAO-A expression. Phytoestrogens with high affinity to ERβ are shown.

Figure 6

Mechanism of diet components and phytochemicals in the regulation of epigenetic modification. Folate, vitamin B₁₂, and genistein increase SAM availability. Curcumin, apigenin, genistein, catechin, EGCG, and luteolin inhibit DNMT, HAT and HDAC. Fisetin, silibinin, and daidzein activate HDAC, leading to regulate gene expression. Some phytochemicals upregulate miRNA or downregulate lncRNA.