Phenolic Acids as Antidepressant Agents

Abstract

Depression is a psychiatric disorder affecting the lives of patients and their families worldwide. It is an important pathophysiology; however, the molecular pathways involved are not well understood. Pharmacological treatment may promote side effects or be ineffective. Consequently, efforts have been made to understand the molecular pathways in depressive patients and prevent their symptoms. In this context, animal models have suggested phytochemicals from medicinal plants, especially phenolic acids, as alternative treatments. These bioactive molecules are known for their antioxidant and antiinflammatory activities. They occur in some fruits, vegetables, and herbal plants. This review focused on phenolic acids and extracts from medicinal plants and their effects on depressive symptoms, as well as the molecular interactions and pathways implicated in these effects. Results from preclinical trials indicate the potential of phenolic acids to reduce depressive-like behaviour by regulating factors associated with oxidative stress, neuroinflammation, autophagy, and deregulation of the hypothalamic-pituitary-adrenal axis, stimulating monoaminergic neurotransmission and neurogenesis, and modulating intestinal microbiota.

Keywords: antiinflammatory; antioxidants; behaviour; depression; medicinal plants; phenolic compounds.

Figure 1

Factors associated with molecular pathophysiology of depression. Illustration of the brain regions involved in dysfunction in the pathophysiology of depression (prefrontal cortex, hippocampus, and hypothalamus). The regions are shown by black arrows and bidirectional communication between the gut (represented by a black arrow) and the human brain. This communication reinforces the importance of the gut microbiota in this neurological disorder. Because of its multifactorial nature verified in several studies, a summary of biological processes (highlighted in blue) and molecular factors (highlighted in red) associated with this disorder is presented in this image. Figure was created using images from Server Medical Art (https://smart.servier.com) accessed on 16 August 2022, licensed under a Creative Commons Attribution 3.0.

Figure 2

Mode of action of monoamine-modulating antidepressants. Selective serotonin reuptake inhibitors, such as fluoxetine, bind to the serotonin transporter (5-HTT) and block the reuptake of this neurotransmitter, whereas antidepressants, such as bupropion, belong to the group of noradrenaline and dopamine reuptake inhibitors. Tricyclic antidepressants, such as amitriptyline, prevent the reuptake of serotonin, dopamine, and noradrenaline in a non-specific manner by binding and blocking their transporters. The α2 adrenergic receptor antagonists, such as mirtazapine, bind to these receptors, increasing noradrenaline levels. Monoamine oxidase (MAO) enzyme inhibitors, such as phenelzine, bind to isoforms of the enzyme, inhibiting its binding to monoamines, thereby blocking its enzymatic catalysis. Figure was created using images from server Medical Art (https://smart.servier.com) accessed on 16 August 2022, licensed under a Creative Commons Attribution 3.0.

Figure 3

Phenolic acids and their pharmacological properties. This image shows the chemical structures of the two main classes of phenolic acids. They are exemplified by caffeic acid (representative derived from cinnamic acid) and gallic acid (representative derived from hydroxybenzoic acid). The schematic representation shows the sources of these bioactive molecules. Caffeic acid has been isolated from medicinal plants, such as Melissa officinalis (lemon balm). Gallic acid is found in fruits and vegetables, such as Allium cepa (onions). Phenolic acids (hydrocinnamic and hydroxybenzoic acids) are a group of bioactive molecules that have several pharmacological effects, including antioxidant, antiinflammatory, antitumor, neuroprotective, and potentially antimicrobial, among others. The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.

Figure 4

Possible mechanisms of action for ferulic acid (a) and gallic acid (b) as antidepressants based on preclinical trials. (a) Ferulic acid may act by inhibiting MAO-A enzyme activity by increasing levels of endogenous antioxidants, combating lipid peroxidation, inhibiting neuroinflammation, and the hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, and increasing levels of brain-derived neurotrophic factor (BDNF) and synaptic plasticity. (b) The antidepressant effects of gallic acid are mainly caused by its antioxidant potential because this promotes the activity of antioxidant enzymes, such as SOD, CAT, and GPx, and increases the content of endogenous antioxidants, such as GSH. The compound also inhibits lipid peroxidation and reduces nitrite levels, demonstrating its action against oxidative and nitrosative stress. Additionally, gallic acid may promote the regulation of the hypothalamic–pituitary–adrenal (HPA) axis because it can reduce elevated corticosterone levels. Its effect is also associated with increased serotonin noradrenaline and dopamine levels in the synaptic cleft. These bioactive molecules may interact with alpha-adrenergic, dopaminergic, and serotoninergic receptors to promote their antidepressant effects. Arrows in red (up) indicate increased levels and (down) reduced levels. The solid black arrow indicates stimulation, and the dashed black arrow indicates possible activation (a mechanism not directly evaluated in the study). The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.

Figure 5

Possible mechanisms of action for chlorogenic acid (a) and caffeic acid (b) as antidepressants based on preclinical trials. (a) Chlorogenic acid may act by increasing levels of monoamine neurotransmitters as an inhibitor of monoamine oxidase isoform B, reducing neuroinflammation, reducing reactive oxygen species production, and improving host gut health by modulating the microbiota. (b) Caffeic acid has been shown to act through the modulation of α1 adrenergic receptors. Takeda et al. [78] suggest that the activation of this receptor, which has a stimulator effect on cell signaling by increasing intracellular phospholipase C (PLC), promotes an increase in Ca²⁺ concentration, thereby activating Ca²/calmodulin-dependent protein kinase (CAMK) and protein kinase C (PKC). These proteins promote phosphorylation of the cAMP response element-binding protein (CREB). Then, CREB regulates BDNF transcription [78]. Another action mechanism might be its inhibitory effect on the inflammatory lipoxygenase (5-LO) pathway, which may reduce monoamine neurotransmitter levels in the synaptic cleft. Additionally, this bioactive molecule might promote the inhibition of the activity of the MAO-A enzyme. The red arrows (up) indicate increased levels and (down) decreased levels. The solid black arrow indicates stimulation, whereas the dashed black arrow indicates possible activation (mechanism not directly evaluated in the study). The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.

Figure 6

Possible mechanisms of action for protocatechuic acid (a) and syringic acid (b) as antidepressants based on preclinical trials. (a) Protocatechuic acid has been shown to have a depressant effect mainly through antioxidant mechanisms. It increases the activity of the enzymes catalase (CAT), superoxide dismutase (SOD), and the amount of glutathione reductase (GSH). Then, it can prevent lipid peroxidation and inhibit oxidative stress. The antidepressant effect of the bioactive molecule is possible because of its potential to reduce neuroinflammation by inhibiting the deregulation of the hypothalamic–pituitary–adrenal (HPA) axis, increasing brain monoamines, and promoting an increase in BDNF levels. (b) Syringic acid promotes antidepressant effect by its antioxidant potential, reducing oxidative stress and nitrosative stress. Another important antidepressant mechanism of this molecule may be associated with glutamatergic excitotoxicity inhibition by PI3K/Akt/GSK-3β neuronal survival pathway activation. Arrows in red (up) indicate increased levels and (down) reduced levels. The solid black arrow indicates stimulation, and the dashed black arrow indicates the possibility of activation (mechanism not directly evaluated in the study). The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.

Figure 7

Possible mechanisms of action for rosmarinic acid (a) and salvianolic acid B (b) as antidepressants based on preclinical trials. (a) The rosmarinic acid action mechanism might be associated with inhibiting monoamine oxidase-A enzyme, thereby increasing BDNF expression in the hippocampal region by negative regulation of MKP-1. This may promote stimulation in hippocampal neurogenesis. Furthermore, it may increase tyrosine hydroxylase expression resulting in increased dopamine and decreased corticosterone levels. This may also be associated with the antidepressant effect of this molecule. (b) The antidepressant effect of salvianolic acid B may be associated with its antiinflammatory effect because this molecule can suppress the expression of proinflammatory cytokines and increase the expression of antiinflammatory cytokines. This response protects against apoptosis and hippocampal atrophy promoted by neuroinflammation. Its antidepressant effect may be associated with the inhibition of microglia and NLRP3 inflammasome activation and autophagy. Additionally, it might modulate corticosterone levels with the normalization of HPA axis hyperactivity, which may be associated with its antidepressant action. Arrows in red (up) indicate increased levels and (down) reduced levels. The solid black arrow indicates stimulation, and the dashed black arrow indicates the possibility of activation (mechanism not directly evaluated in the study). The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.

Figure 8

Possible mechanisms of action for ellagic acid as antidepressant based on preclinical trials. Studies have shown an association between serotoninergic, 5-HT1A/B, 5-HT2A/2B, and 5-HT3 receptors, and α-1 and α-2 adrenergic receptors in the antidepressant action of ellagic acid. Ellagic acid increased BDNF levels in the hippocampus. Its effect on the glutaminergic NMDA receptor was verified by modulating the expression of NR2A and NR2B subunits. This bioactive molecule may reduce the NO levels. This molecule may inhibit the NMDA-NO pathway and reduce nitric oxide levels, playing a part in the ellagic acid antidepressant effect. The red arrows (up) indicate increased levels and (down) reduced levels. The solid black arrow indicates stimulation, and the dashed black arrow indicates the possibility of activation (mechanism not directly evaluated in the study). The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.

Figure 9

Overall summary, with the main possible molecular mechanisms by which phenolic acids may reduce depressive-like behaviour in rodents. T-shaped arrows stand for inhibition and normal arrows for stimulation. Figure was created using image from Servier Medical Art (https://smart.servier.com) accessed on 16 August 2022, licensed under a Creative Commons Attribution 3.0. The chemical structures were drawn using ChemSketch freeware, version 14.0 from ACD/Labs.