Phytochemicals That Act on Synaptic Plasticity as Potential Prophylaxis against Stress-Induced Depressive Disorder

Abstract

Depression is a neuropsychiatric disorder associated with persistent stress and disruption of neuronal function. Persistent stress causes neuronal atrophy, including loss of synapses and reduced size of the hippocampus and prefrontal cortex. These alterations are associated with neural dysfunction, including mood disturbances, cognitive impairment, and behavioral changes. Synaptic plasticity is the fundamental function of neural networks in response to various stimuli and acts by reorganizing neuronal structure, function, and connections from the molecular to the behavioral level. In this review, we describe the alterations in synaptic plasticity as underlying pathological mechanisms for depression in animal models and humans. We further elaborate on the significance of phytochemicals as bioactive agents that can positively modulate stress-induced, aberrant synaptic activity. Bioactive agents, including flavonoids, terpenes, saponins, and lignans, have been reported to upregulate brain-derived neurotrophic factor expression and release, suppress neuronal loss, and activate the relevant signaling pathways, including TrkB, ERK, Akt, and mTOR pathways, resulting in increased spine maturation and synaptic numbers in the neuronal cells and in the brains of stressed animals. In clinical trials, phytochemical usage is regarded as safe and well-tolerated for suppressing stress-related parameters in patients with depression. Thus, intake of phytochemicals with safe and active effects on synaptic plasticity may be a strategy for preventing neuronal damage and alleviating depression in a stressful life.

Keywords: Depression; Phytochemicals; Preventive agents; Stress; Synaptic plasticity.

Fig. 1

The major signaling pathways involved in regulating spine remodeling and synaptic plasticity, including the NMDA and AMPA glutamate receptor subtypes, neurotrophic factors (i.e., BDNF), and related downstream signaling. (A) Repeated stimulations or strong signals induce the release of neurotransmitters such as glutamate at the presynaptic terminals of the neuron. Glutamate released from presynaptic terminals binds to its receptors (e.g., AMPA, NMDA, mGlu) leading to the release of ions (e.g., calcium, sodium) into the synaptic cleft and AMPAR phosphorylation, which results in the induction of LTP in postsynaptic neurons. Calcium influx through NMDARs and somatic voltage-dependent calcium channels (VDCCs) activate Ca²⁺/calmodulin-dependent kinase (CaMK) isoforms, cyclic AMP, and phosphatidylinositol pathways, inducing the activation of cyclic AMP-responsive element-binding protein (CREB); this promotes BDNF expression. In dendrites, BDNF is packaged into secretory granules for the regulated secretion pathway and released into the synapse. When secreted BDNF binds its receptor, TrkB, phosphorylated TrkB activates the downstream protein, Akt, followed by the activation of mTOR by p-Akt. Then, mTOR activates two downstream signaling proteins, p70s6k and 4E-BP, and controls local translational activation and local proteins synthesis (GluA1, PSD95) enhancement. (B) Conversely, LTD can be induced by repeated low-frequency stimulation. Weak activity of presynaptic neurons leads to modest depolarization and calcium influx through the NMDA receptors. This preferentially activates phosphatases (protein phosphatase1, PP1), which dephosphorylate AMPA receptors, thus promoting receptor endocytosis and decreased efficacy of the synapse. Chronic stress decreases BDNF and mTORC1 signaling, in part via upregulation of the negative regulator ‘regulated in DNA damage and repair’ (REDD1), which decreases the synthesis of synaptic proteins and thereby contributes to a reduced number of spine synapses.

Fig. 2

Phytochemicals that target synaptic plasticity signaling in stress-induced, depressive animals. Many phytochemicals can increase hippocampal BDNF levels and stimulate TrkB receptor and its downstream factors, ERK, Akt, and mTOR; CREB/BDNF/TrkB signalings are associated with synaptic plasticity and antidepressive effects. (1) Apigenin, (2) baicalein, (3) 7,8-dihydroxyflavone, (4) nobiletin, (5) rutin, (6) fisetin, (7) naringenin, (8) quercetin, (9) dihydromyricetin, (10) hesperidin, (11) curcumin, (12) S-equol, (13) silibinin, (14) puerarin, (15) paeoniflorin, (16) resveratrol, (17) honokiol, (18) (-)-gallocatechin gallate, (19) gallic acid, (20) malvidin3’-O-glucoside, (21) ginsenoside, (22) oleanolic acid, (23) hyperforin, (24) psilocybin, (25) cytisine, (26) isorhynchophylline.