Monoamine neurotransmitters are essential for signal transduction in the central nervous system (CNS) and play a role in regulating movement, basal muscle tone, activity levels, emotions, attention, sleep, vascular tone, circulation, thermoregulation, and pain modulation (Ng et al., 2015). Fewer than one percent of neurons in the human brain can produce and release the neurotransmitter 5-hydroxytryptamine (5-HT, also named serotonin), a characteristic shared by all such neurons. Despite their limited number, 5-HT neurons extensively innervate the majority of brain regions and the spinal cord, contributing to a diverse array of neurological processes (Okaty et al., 2019).

Dopamine (DA) neurons regulate many important behaviors in behaviorism, including reinforcement, aversion, social reward, and responses. These functions are related to the different connectivity patterns of different subgroups of DA neurons at the molecular level. The genetic diversity, projection specificity, and functional responses of DA neurons are consistent, which may contribute to heterogeneity in the behavioral phenotypes of affective disorders and varying responses to treatment (Wu et al., 2024). Norepinephrine (NE) can directly interact with immune cells, influencing their signaling pathways and metabolic processes. In both primary and secondary lymphoid organs, NE functions as both a neurotransmitter and a neuromodulator. When sympathetic nerve terminals release NE, it immediately binds to adrenergic receptors on immune cells within these organs. Similarly, circulating adrenaline produced by the adrenal gland can interact with adrenergic receptors. Additionally, neurons express cytokine and chemokine receptors released by the immune system, facilitating the precise modulation of local immune responses (Thoppil et al., 2023). Dysregulation of monoamine neurotransmitters can have negative effects on the body.

PSD correlates with decreased concentrations of the biogenic monoamines 5-HT, DA, and NE in the CNS. The main monoaminergic nuclei are located in the brainstem, and their ascending projections extend throughout the brain, including the cortex and limbic system (Medeiros et al., 2020). During a stroke, ischemic lesions disrupt projections from the midbrain and brainstem, reducing the bioavailability of 5-HT, DA, and NE. These lesions may damage axons carrying biogenic amines from the brainstem to the cerebral cortex, leading to decreased levels of these neurotransmitters in the frontal and temporal lobes, as well as in peripheral tissues and the basal ganglia. The monoamine hypothesis suggests that depression correlates with decreased levels of monoamines, particularly 5-HT, NE, and DA (Loubinoux et al., 2012).

The pathophysiological mechanisms of PSD are multifactorial. Therefore, the establishment of an effective middle cerebral artery occlusion (MCAO) animal model or other suitable experimental animal models can facilitate the study of depression, particularly PSD (Ifergane et al., 2018; Kronenberg et al., 2014). Researchers can capture key aspects of PSD through animal models, thereby assessing behavioural performance and underlying neurobiological changes (Mușat et al., 2024).

Based on preclinical studies such as MCAO rats, it was shown that stimulation of small conductance calcium-activated K⁺ channels (SK channels) may enhance the expression of DA neurons in the ventral tegmental area (VTA) of PSD rats, resulting in behavioral changes associated with depression. In contrast, inhibition of SK channels may reduce the expression of DA neurons in the VTA, thereby alleviating depression-related behaviors. A clear association has been observed between the activation of SK channels in the VTA of PSD rats and the exacerbation of depression-related behaviors (Wang et al., 2023). Additionally, MCAO and the decrease in DA neuron density in the VTA are closely linked to a reduction in DA concentration in the brain, which is strongly associated with depression-like symptoms that can emerge during the middle stage of stroke in neonatal rats (Villa et al., 2023).

Based on the regulation of neurotransmitters, PSD can be improved. The expression of 5-HT transporter genes is elevated in the hippocampus and frontal cortex following MCAO, and SSRIs have shown efficacy in the therapeutic management of PSD (Brait et al., 2022). Unilateral ischemic lesions in the medial prefrontal cortex reduce the innervation of 5-HT and NE in the affected area, as well as in other brain regions distal to the stroke. The plasticity of 5-HT axons in the forebrain projection induced by fluoxetine may help facilitate the recovery of brain injury (Zahrai et al., 2020). It can be inferred that the imbalance of monoamine neurotransmitters is an important factor contributing to PSD (Figure 2).

Corticotropin-releasing hormone (CRH), produced and secreted by the hypothalamus, regulates the production of pituitary adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal cortex to release glucocorticoids (Werdermann et al., 2021). However, during stress events, the HPA axis becomes overactivated, leading to the release of excess glucocorticoids into the bloodstream. Numerous studies have shown that elevated levels of glucocorticoids in the hippocampus exert negative feedback regulation on the HPA axis via glucocorticoid receptors (GR), which is essential for maintaining the homeostasis of the HPA axis. The hypothalamic axis plays a key role as an adaptive system that allows the body to respond to urgent physiological and psychological challenges. Overactivity of the HPA axis has been strongly linked to the pathology of depression (Liu M. Y. et al., 2023).

The HPA axis is one of the dysregulated systems in depression, with ample evidence supporting its association with depression and other stress-related disorders. The sensitivity of GRs is primarily modulated by FK506 binding protein 5, which is linked to several mental illnesses and stress-related conditions, including severe depression, bipolar disorder, childhood trauma, post-traumatic stress disorder, as well as violent and suicidal behaviors (Menke, 2019).

CRH is one of the primary signaling peptides released after HPA axis activation during stress. As an autophagy associated protein, p62 participates in the Keap1-Nrf2 pathway through its Keap1 interaction. Recent experimental studies using the MCAO-established animal model of PSD have shown that CRH induces p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonists can inhibit the Keap 1-Nrf 2-p62 pathway by attenuating oxidative stress. These antagonists alleviate depression-like behavior and prevent hippocampal synaptic loss in PSD rats by removing excess p62, making them a new target or emerging mechanism for treating PSD (Liu et al., 2024).

HPA axis hyperfunction is one of the pathological mechanisms of PSD. Studies indicate that the severity of depression is positively associated with the level of HPA axis activation (He et al., 2003). Stroke-induced HPA axis hyperfunction significantly contributes to PSD, initiating a cascade of complex events within the neuroendocrine system, including the HPA axis. The activation of the HPA axis after a stroke is primarily driven by stress and the secretion of pro-inflammatory cytokines following significant brain damage. The involvement of HPA axis hyperactivity in PSD includes the influence of elevated ACTH, the impact of glucocorticoids on specific brain structural alterations, enzyme expression, excitotoxicity, changes in intestinal permeability, and microglial activation. These factors contribute directly or indirectly to the pathological progression of depression (Zhou et al., 2022). There is a bidirectional relationship between HPA axis dysfunction and levels of inflammatory cytokines. High cortisol levels induce inflammatory responses, which in turn exacerbate HPA axis dysfunction (Li et al., 2014). Dysregulation of the HPA axis and elevated pro-inflammatory cytokine levels may impair neurogenesis in the hippocampus, reduce neural plasticity in the prefrontal cortex, and contribute to the onset and persistence of PSD (Koo et al., 2010).

The stimulation of the HPA axis increases the concentration of glucocorticoid hormones, particularly cortisol, in the bloodstream (Douglass et al., 2023). There is a risk of developing depression if high cortisol levels persist for 3 months after a stroke. Chronic stress following a stroke may enhance the adrenal gland’s sensitivity to ACTHs, thereby prolonging hypercortisolism, which has numerous negative effects. Therefore, stroke events may serve as a key trigger for the activation of HPA axis stress in patients during the later stages, and the stimulation of the HPA axis in response to stress may contribute to the onset of depression (Aström et al., 1993).

On the other hand, in the early stages following a stroke, hypercortisolism may result from changes in cortisol metabolism and/or clearance, an enhanced adrenal gland response to ACTH, or reduced efficacy of the negative feedback mechanism between cortisol and the hypothalamus (Olsson et al., 1992). The changes in the HPA axis are part of neuroendocrine alterations, and the main neuroendocrine changes after a stroke involve the activation of the HPA axis. In some individuals, significant alterations in these neuroendocrine pathways may negatively affect functional outcomes, cognition, and emotions. Specific sequelae of stroke, like depression and sleep difficulties, may be influenced by endocrine changes, which could potentially be modified if relevant neuroendocrine abnormalities are identified and addressed (El Husseini and Laskowitz, 2014).

Focal brain injury leads to excessive activation of inflammation, disrupts HPA axis control, and further increases hormone secretion, resulting in changes in the expression and properties of cortical hormone receptors in key brain structures (primarily the limbic system). This alteration modifies the regulatory mechanism of the entire negative feedback control system (Zhanina et al., 2022). Reports indicate that CRH neurons in the paraventricular nucleus possess 5-HT receptors, suggesting a potential interaction between the HPA axis and affective disorders or stress (Heisler et al., 2007). From this, it can be concluded that the regulation of HPA axis dysfunction is intricately linked to PSD, and that interventions targeting the HPA axis offer a viable strategy for addressing PSD.

Glu serves as the primary excitatory neurotransmitter in the brain, essential for maintaining proper neuronal activity. Glu plays a crucial role in perception, including learning, memory, and other behavioral functions (Pasanta et al., 2023). Glu primarily interacts with two types of receptors: ionotropic receptors and G protein-coupled metabotropic receptors. Under physiological conditions, the activation of these receptor subpopulations induces excitatory synaptic transmission and processes associated with synaptic plasticity, such as long-term potentiation/depression, which are molecular mechanisms underlying learning and memory. Upon Glu binding, the ionotropic Glu receptor facilitates fast excitatory neurotransmission through its ion channel activity, allowing Na⁺ and K⁺ cations to traverse the plasma membrane and generate action potentials. After activation, Glu is removed from the synaptic cleft by excitatory amino acid transporters, thus terminating synaptic transmission and enabling subsequent action potentials (Neves et al., 2023).

Glu is the predominant free amino acid in the brain, positioned at the intersection of many metabolic pathways. Moreover, Glu has an excitatory effect on neuronal cells, which can lead to cell death in a process known as “excitotoxicity” (Zhou and Danbolt, 2014). Excitotoxicity is crucial in the pathophysiology of several neurodegenerative disorders, including depression. The toxic effects of excitatory neurotransmitters, particularly Glu, can induce neurotoxicity, resulting in impaired neuronal function and subsequent brain damage (Armada-Moreira et al., 2020). At the same time, the increased release of Glu can induce stress and contribute to numerous neurodegenerative disorders. Li et al. suggest that disruptions in Glu neurotransmission may contribute to the development of various mental disorders and abnormalities, including major depression (Li et al., 2019).

On the other hand, stroke is associated with a significant increase in extracellular fluid and cerebrospinal fluid Glu levels. Glu diffuses and induces neuronal injury in areas adjacent to the infarcted tissue. Excessive Glu in the brain’s extracellular fluid can activate Glu receptors, resulting in cellular swelling, apoptosis, and neuronal death. Plasma Glu levels are positively correlated with the severity of depressive symptoms in individuals with severe depression (Frank et al., 2019). Elevated levels of Glu have been found in the serum of PSD patients (Cheng et al., 2014). The association between glutamate excitotoxicity and PSD is correlative, but it needs to be further verified in subsequent experiments. In preclinical experiments, valproate (VPA) or lamotrigine (LTG), two drugs that prevent glutamate-mediated excitotoxicity by increasing inhibitory inputs or blocking sodium channels, were found to correct depressive-like behaviour to some extent with early treatment (Li et al., 2020).

Due to the widespread diffusion of Glu beyond the infarcted tissue, this increase can cause neuronal damage. Feng et al. found that the size of the infarction is a crucial factor determining the severity of PSD (Feng et al., 2014). Therefore, an elevation in Glu may impair blood flow to necrotic cerebral tissue (cerebral infarction), leading to extensive damage. The overproduction of Glu activates its receptors, resulting in cellular swelling and initiating neuronal apoptosis, eventually leading to cell death through the activation of calcium-dependent enzymes (Gruenbaum et al., 2020).

Dysregulation of the Glu system is key for the neurobiology of depression. Studies show the presence of Glu receptor proteins in the prefrontal and temporal cortices of individuals with PSD,indicating glutamatergic dysfunction (Khoodoruth et al., 2022). Substantial evidence suggest that disruptions in Glu signaling can easily lead to emotional disorders, including PSD.

Oxidative stress significantly contributes to the pathogenic processes of several types of depression, including PSD. Extensive activation of Glu receptors triggers excitotoxicity, leading to cerebral imbalance and elevated production of free radicals to toxic levels. Free radicals, which are highly reactive atoms and molecules, can damage proteins and other cellular structures (Rama et al., 2016). In addition, they also trigger mitochondrial dysfunction and neuronal damage, exacerbating excitotoxic cell death in the brain after stroke. Some free radicals (such as superoxide/hydroxyl radicals), are generated through excitotoxicity. The degeneration of neurons impairs the transmission of sensory information, including emotional regulation (Naghavi et al., 2019), which is linked to severe mental disorders like PSD after a stroke. Therefore, preventing and regulating Glu-mediated neurotoxicity is crucial for both the prevention and treatment of PSD.

The neural circuit is a structured system capable of transmitting and process incoming information. These circuits are also adaptable, capable of substantial enhancement and reorganization in response to development, environmental stimuli, pain, or injury (Walter et al., 2023). The dynamic remodeling of neural circuits is an ongoing process that influences neuronal activity, and disruption of this process can lead to mental illnesses. In the human brain, neurons are interconnected by billions of synapses within the CNS. The brain’s functionality depends on the exchange and transfer of information between these synapses, with the resulting neural activity providing excitation, inhibition, or regulatory signals. The pathways that transmit information between neurons are known as neural circuits, which create intricate networks within various brain regions. Any alteration in these paths can serve as a sensitive indicator of the changes in the neural circuit (Xiong et al., 2023).

Resting-state functional connectivity (FC) is useful for evaluating synchronous patterns of spontaneous neuronal activity and offers insights into the interconnections across areas within neural circuits or networks (Zhong et al., 2018). Research utilizing resting-state FC has shown that Parkinson’s disease (PD) is associated with alterations in various networks, including the default mode network (DMN) (posterior cingulate cortex seeds), emotional networks (anterior cingulate cortex [ACC] seeds), and cognitive control networks (dorsolateral prefrontal cortex seeds) (Balaev et al., 2018; Shi et al., 2017a; Vicentini et al., 2017; Zhang P. et al., 2018). The selected seeds for functional connectivity analysis mostly pertain to the disruption of severe depression, overlooking the impact of localized brain damage as the principal cause of PSD. The lesion site of PSD is commonly associated with the depression circuitry, particularly the left dorsolateral prefrontal cortex (DLPFC). Depressed individuals show a significantly stronger correlation with these lesions compared to non-depressed individuals. After a stroke, PSD patients demonstrate specific changes in their depression circuitry, including increased connectivity between the bilateral lingual gyrus and superior frontal gyrus, as well as between the contralateral middle frontal gyrus and ACC with the DLPFC (Fan et al., 2023).

The limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit is closely related to emotion regulation (Sheline, 2003). This circuit originates from the DLPFC, projects to the new striatum and thalamus, and then loops back to the cortex, primarily involving the limbic system, cortex, striatum, white matter, and thalamus (Tekin and Cummings, 2002). The proper functioning of the LCSPT circuit requires the integrity of white matter fibers in the brain. Disruption of white matter integrity impairs the LCSPT circuit, potentially leading to emotional disorders, such as depression. Microstructural damage to the white matter in regions like the frontal lobe (particularly the DLPFC), temporal lobe, and knee of the corpus callosum may contribute to the onset of PSD, with the severity of white matter damage correlating to the intensity of PSD (Liang et al., 2021).

PSD is characterized by reduced mutual inhibition between the functional circuits of the nucleus accumbens (NAc) and the DMN, along with changes in volume and microstructure within these networks. Consequently, the atypical network dynamics observed in individuals with PSD may be influenced by subsequent and extensive alterations in gray and white matter, even in regions distant from the lesion site. The disrupted link between reward processing and the DMN provides a plausible explanation for the development of post-stroke depressive symptoms. Alterations in blood oxygen level dependent signals suggest that the NAc is functionally linked to various subcortical structures, as well as medial frontal and temporal cortical areas. Similarly, the DMN encompasses a widespread regional network across the frontal and parietal cortices. Structural lesions in different areas may disrupt functional connections both within and across these networks (Oestreich et al., 2022).

The ACC is a key structure associated with emotional processing. As part of the brain’s limbic system, the ACC integrates with the limbic cortex (Passarotti et al., 2010) and plays a crucial role in emotional networks, including the DMN and attention networks. It has extensive neuronal connections to the amygdala, thalamus, and hippocampus (Enzi et al., 2012). When used as a seed for connectivity analysis, the ACC exhibits a significant reduction in FC with the prefrontal cortex, cingulate cortex, and motor cortex, alongside an increase in connectivity with the hippocampal gyrus, parahippocampal gyrus, insula, and amygdala. The stroke-affected area reduces excitability in the ipsilateral brain region, impacting emotional regulation through the prefrontal-limbic circuit and contributing to the onset of depression (Shi et al., 2017b). These findings suggest that varying degrees of neural circuit damage occur in PSD patients, and maintaining the stability of neural circuits is an effective way to improve PSD.

Neuroplasticity, often referred to as “brain plasticity,” is characterized as any alteration in the neural system that occurs throughout an individual’s lifespan. This means the nervous system can undergo changes in various ways. Neuroplasticity refers to the alterations in the nervous system induced by experience, including its ability to adapt to internal or external stimuli via the reorganization of its structure, function, and connections (Axelrod et al., 2023). Neuroplasticity is interconnected in several ways and can be seen as a continuous cycle of human activity that modifies brain connections and influences behavior (Wallace et al., 2023). It is key to understanding brain development, learning, and the regulation of CNS homeostasis. Broadly speaking, “neuroplasticity” refers to the ability of neural tissue to undergo changes in both normal function and pathological processes. The mechanisms of neuronal plasticity include the regulation of synaptic strength (i.e., synaptic plasticity), structural remodeling, as well as the regulation of intrinsic characteristics of neurons, like excitability or firing rate (Dzyubenko and Hermann, 2023).

The changes in neurotrophic factors lay the basis for impaired neural plasticity, which is directly linked to the onset and progression of depression. Antidepressant therapies are believed to exert their beneficial effects by enhancing the nutritional signals that promote neuronal and synaptic plasticity (Levy et al., 2018). Neurotrophic growth factors and their associated signaling pathways are primary contributors to brain plasticity, and dysfunction in these pathways is often correlated with depressive symptoms (Pittenger and Duman, 2008). Brain-derived neurotrophic factor (BDNF) is a key neurotrophic factor that plays a crucial role in neuronal development, differentiation, and survival. It is also involved in the regulation of neurogenesis and synaptic plasticity (Lu et al., 2014).

Growth factors and associated neurotrophic signals are essential for the growth and maintenance of the CNS (Greenberg et al., 2009). Abnormal nutritional support in the cortical regions that regulate emotions and mood may contribute to the pathophysiology of depression (Krishnan and Nestler, 2008). In addition, antidepressants require brain plasticity pathways to correct impairments in neuronal and synaptic plasticity, which are often linked to emotional disorders (Pittenger and Duman, 2008).

The concept of neuroplasticity suggests that the depletion of BDNF significantly contributes to the pathophysiology of PSD, and its restoration may be a crucial mechanism behind the effectiveness of antidepressant medications. BDNF, a member of the neurotrophic factor family, is expressed in both the central and peripheral nervous systems, with the highest expression observed in the cortex and hippocampus. Clinical studies indicate that variations in blood BDNF levels may serve as an early marker of depression in stroke patients. However, the use of BDNF as a marker still needs to be further refined in subsequent studies. Reduced BDNF levels in the prefrontal cortex and hippocampus correlate with the onset of PSD, and elevating BDNF levels in the prefrontal cortex may serve as a crucial intervention for treating PSD (Chen et al., 2020).

BDNF serves as a neurotrophic agent for DA neurons in the substantia nigra, promoting the survival of cultured human and rat midbrain dopaminergic neurons. Preclinical studies have shown that long-term infusion of BDNF into the midbrain of rats increases levels of BDNF in several regions, including the neocortex. Additionally, it enhances the turnover rate of 5-HT and the level of NE in many forebrain regions, such as the basal ganglia and hippocampus. Infusion of BDNF into the periaqueductal gray matter and dorsal or substantia nigra has antidepressant-like effects (Youssef et al., 2018).

Disruptions in BDNF signaling are linked to neurological diseases, such as major depression. In fact, serum BDNF levels are decreased in patients with PSD. Studies indicate that elevated BDNF protein levels in the hippocampus may mitigate behaviors linked to depression. The decreased expression of BDNF in the hippocampus, which affects neural plasticity, synaptic architecture, and function, suggests that low BDNF levels contribute to a decline in hippocampal neurogenesis, leading to PSD (Chen et al., 2015). Therefore, increasing BDNF levels to repair neural plasticity is a promising approach for treating PSD. However, upstream/downstream signaling components and their phenotypic manifestations in brain cells have not been well clarified in current BDNF research, which is mostly experimental. Furthermore, the lack of evidence linking serum BDNF levels to concentrations in the CNS limits the therapeutic significance, and further research is necessary to determine the causal linkage between peripheral and central BDNF.

Damage to the neuroimmune system can significantly impact PSD, with particular emphasis on neutrophils and neuroinflammation. Neutrophils, a type of myeloid white blood cell, are key responders to acute inflammation. They serve as the primary defense mechanism of the host against various pathogens, including bacteria, fungi, and protozoa. The localization of neutrophils at the site of infection is crucial; therefore, a decrease in neutrophil levels in the blood can lead to severe immune deficiencies in humans (Liew and Kubes, 2019).

Neuroinflammation in the brain is an innate immune response primarily mediated by reactive glial cells (astrocytes and microglia), which secrete cytokines, chemokines, reactive oxygen species (ROS), and other pro-inflammatory mediators (Sanz et al., 2024). These substances can affect neuronal activity in both the surrounding and CNSs (Li et al., 2024).

After stroke, both astrocytes and microglia undergo a series of morphological and functional changes. Due to the phenotypic transformation of astrocytes and microglia, A1/A2 and M1/M2, different subtypes of microglia and astrocytes play different roles in PSD. Astrocytes and microglia in the CNS play an important role in the pathological process of PSD by producing cytokines such as interleukin (IL), tumor necrosis factor (TNF) and interferon (IFN) (Ogłodek, 2022; Wang L. et al., 2019; Lu and Wen, 2024).

The gastrointestinal system interacts with the brain in a reciprocal relationship known as the GBA. The brain regulates gut function through the HPA axis and the autonomic nervous system. Conversely, the gut influences CNS function by utilizing various microbial-derived metabolites, neuroactive substances, and gut hormones, which are transmitted to the brain via the enteric nervous system, the vagus nerve, the circulatory system, or the immune system (Liu et al., 2022). Resident microbial communities in the gut are key regulators of the GBA. These communities, which include bacteria, fungi, viruses, and other living organisms, are collectively referred to as the microbiome (Davenport et al., 2017).

The microbiota may impact the CNS, particularly by fostering bidirectional interactions between the brain and gut. The brain and gut can influence each other’s activities through neuroendocrine, neuroimmune, and sensory molecular pathways mediated by the microbiota (Wilkowska et al., 2021; Lach et al., 2018). The relationship between the brain and gut microbiota (GM) may profoundly affect stress, anxiety, cognition, and neuropsychiatric conditions such as depression, bipolar disorder, schizophrenia, and anxiety (Limbana et al., 2020; Nikolova et al., 2021).

Intestinal peptides modulate endocrine function and may interact with the CNS. Research on these peptides not only pertains to dietary consumption but also to stress-related behaviors and responses to such circumstances. The composition of GM can affect the permeability of the intestinal barrier, resulting in the secretion of gut peptides that enter brain cells in different ways and exert different effects. This variation may indicate distinct roles of peptides in organisms. Such differences can lead to changes in behaviors, ranging from reduced emotional engagement to depression-like behaviors (Lach et al., 2018).

Studies in both humans and animals indicate potential changes in the GM composition between healthy individuals and those with depression. The most significant association is the Firmicutes/Bacteroidetes ratio. In preclinical animal studies, it was found that rodents with higher levels of Bacteroidetes and lower levels of Firmicutes in the gut tended to exhibit depression-like behaviours (Labus et al., 2017; Yu et al., 2017).

The composition of the GM may influence the release of gut peptides and regulate the balance of the endocrine system. Excessive secretion of pro-inflammatory cytokines can alter the GM, as these cytokines affect gut peptides that are absorbed via the permeable intestinal barrier. This imbalance in the quantity of peptides reaching the brain may serve as a catalyst for alterations in the microbiota, resulting in behaviors resembling depression (Młynarska et al., 2022).

The changes in microbial communities within and between individuals are key drivers of stroke risk factors. An experimental analysis of the oral and fecal microbiota in African American participants from various countries revealed that individuals with cerebrovascular risk factors, like hypertension, hyperglycemia, along with hypertriglyceridemia, had high levels of oral Streptococcus, Prevotella, and Klebsiella (Fei et al., 2019). A study involving 100 patients with atherosclerosis showed that plasma levels of tryptophan, indole, indole-3-propionate, as well as indole-3-aldehyde were inversely linked with the progression of atherosclerosis (Wikoff et al., 2009). In contrast, the ratio of canine uric acid to tryptophan was positively associated with atherosclerosis (Cason et al., 2018). It suggests that the metabolic diversion of tryptophan from the indole pathway (controlled by bacteria) to the kynurenine pathway (regulated by the host) may negatively affect atherosclerosis, a significant risk factor of stroke. These findings indicate that the GM may be involved in the development of significant risk factors of stroke (Honarpisheh et al., 2022).

In animal experiments, comparisons of the GM and fecal metabolomics between PSD rats, control rats, and stroke rats revealed that compared to the control and stroke groups, the microbial phenotype of PSD rats was different. Moreover, changes in the operational taxonomic units of GM were strongly correlated with a variety of metabolites. In addition, the alterations in the gut flora of PSD rats were closely correlate with their behavioral expressions. Enrichment analysis identified essential metabolic pathways linked to PSD. These findings indicate that the GM may play a role in the onset of PSD, with its mechanism potentially involving the regulation of lipid metabolism (Jiang et al., 2021).

In a fecal sample testing experiment involving patients with acute ischemic stroke, the genus Streptococcus was significantly increased in PSD patients. This includes taxonomic groups with relatively higher abundance, including strains with inflammatory characteristics, suggesting the presence of potential inflammatory mediators between GM and PSD. In addition to investigating potential pathogens, researchers also observed a decrease in bacterial abundance in PSD patients, including Shigella flexneri, Clostridium butyricum, and Waldmann’s bacteria (Yao et al., 2023). An increase in pathogenic bacteria, along with a reduction in beneficial microorganisms within the GBA, may serve as risk factors for PSD (Figure 4).

Gastrodin, the active ingredient in G. elata Bl., exhibits antidepressant properties (Chen et al., 2016). In assay experiments using rat microdialysate samples, three MANTs—DA, 5-HT, and L-DOPA showed significantly different dynamic concentration changes in PSD model rats. These changes were synchronized with the hematological metabolism of gastrodin (200 mg/kg) following oral administration. A SILD-MDSPE-UHPLC-MS/MS method was developed to precisely quantify trace neurotransmitters in rat brain microdialysis fluids by generating isotopically labeled m/z 413.3/416.3 and m/z 429.4/432.4 product-specific ions from d₀- or d₃-MRSF-labeled MANTs and aromatic amino neurotransmitters, respectively, for multiple reaction monitoring detection. The findings suggest that gastrodin has a regulatory effect on brain neurotransmitters comparable to that of fluoxetine and may serve as a promising herbal agent for the treatment of PSD (Zhao et al., 2019).

Huperzine A (HupA), an alkaloid derived from the traditional Chinese medicine Huperzia serrata (Thunb. ex Murray) Trevis., is a highly promising clinical drug (Wang et al., 2006). It not only inhibits acetylcholinesterase but also provides neuroprotective benefits against brain ischemic damage (Zhou et al., 2001) and improves cognitive dysfunction in major depression (Zheng et al., 2016). Following the injection of HupA, the sucrose preference of PSD rats in the sucrose preference test was significantly increased, but their resting time in the forced swimming test was dramatically decreased. HupA treatment demonstrated obvious antidepressant effects, enhancing neurological and cognitive functions in PSD rats. It was associated with the upregulation of 5-HT 1A receptor, p-CREB, as well as BDNF expression in the hippocampus, along with increased levels of 5-HT in the hippocampus and prefrontal cortex and elevated DA and NE levels in these regions. These findings indicate that HupA alleviates depressive symptoms in PSD rats, highlighting its potential antidepressant properties (Du et al., 2017).

Astragaloside VI (AsVI), a compound derived from Astragalus membranaceus (Fisch.) Bunge, exhibits neuroprotective effects against cerebral ischemic injury (Liu et al., 2015) and promotes axonal regeneration and neuronal synapse reconstruction (Yang et al., 2013). In vitro, AsVI enhances cell proliferation and migration by activating the epidermal growth factor receptor/extracellular signal-regulated kinase (EGFR/ERK) signaling pathway, while in vivo, it accelerates both sterile and infected wound healing (Lee et al., 2018). In PSD rats, AsⅥ treatment significantly reduced depressive-like behavior and mitigated corticosterone (CORT)-induced apoptosis in neuronal PC-12 cells. Additionally, AsVI therapy effectively prevented the decline of DA and 5-HT levels in the brains of PSD rats and in CORT-induced PC-12 cells. Moreover, AsⅥ activated the neuregulin-1-mediated mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK/ERK) pathway, which correlated with PSD improvement. These findings indicate that AsⅥ alleviates depressive behaviors both in vitro and in vivo by increasing neurotransmitter levels and inhibiting neuronal apoptosis, highlighting its potential as a novel therapeutic option for PSD (Chen X. et al., 2022).

Naringin, a flavonoid found in the fruits of Citrus reticulata Blanco, a grapefruit species, has anti-inflammatory, anticancer, lipid-lowering, and antioxidant properties (Choi et al., 2001), as well as neuroprotective effects (Gaur et al., 2009; Kumar and Kumar, 2010). Naringin therapy significantly reduces oxidative damage by lowering malondialdehyde (MDA) and nitrite levels, restoring depleted glutathione concentrations, and enhancing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST), indicating its antioxidant efficacy. At the cellular level, naringin alleviated the harmful effects of ROS by directly upregulating the transcription of genes encoding antioxidant enzymes, including CAT, SOD, and glutathione peroxidase (Harkin et al., 2004). Furthermore, naringin significantly restores mitochondrial enzyme activities, suggesting its role in mitochondrial function. Pretreatment with L-NAME or 7-NI further enhanced its protective effects by restoring mitochondrial enzyme activities, highlighting the involvement of nitric oxide in its neuroprotective actions. These findings suggest that naringin plays a crucial role in counteracting neurobehavioral, biochemical, and cellular changes in depressed mice following stroke (Aggarwal et al., 2010).

Rosmarinic acid (RA) is a potent polyphenol widely distributed among plant groups such as Labiatae, Seaweeds and Ferns (Petersen and Simmonds, 2003; Lee et al., 2016). RA has strong anti-inflammatory (Grigoletto et al., 2016) and antioxidant properties (Fujimoto et al., 2010; Fonteles et al., 2016). Nrf2 is a major regulator of the antioxidant signaling system. Under stress conditions, Nrf2 separates from Keap1 and translocates to the nucleus, where it initiates the transcription of antioxidant enzyme genes, thereby promoting cellular protection. Nrf2 knockdown abolished the RA-induced elevation of SOD and CAT activity, suggesting that the neuroprotective effect of RA in PSD may be compromised by the downregulation of Nrf2. These findings indicate that the Nrf2 antioxidant pathway may contribute to the antidepressant effects of RA therapy. Ischemia-reperfusion injury significantly reduced the activities of SOD and CAT, along with glutathione (GSH) levels; however, RA treatment mitigated these reductions. The protective effect of RA against ischemia-reperfusion was largely attributable to its antioxidant properties. Consequently, RA markedly reduced neurological impairments and infarct volume. RA therapy alleviated depressive behaviors by preventing the decline of SOD and CAT activities and preserving GSH levels in the brain (Wang J. et al., 2021).

Resveratrol (RES) is a polyphenolic compound and phytoantimicrobial primarily found in the skins of red wine grapes, Reynoutria japonica Houtt., and certain nuts. It exhibits anti-inflammatory, antioxidant, as well as anticarcinogenic properties (Gambini et al., 2015) and provides neuroprotection after stroke (Hou et al., 2018). In PSD rats, RES treatment led to reduced cytoplasmic Nrf2 expression and increased total Nrf2, heme oxygenase-1 (HO-1), and nuclear Nrf2 (N-Nrf2) protein levels, suggesting enhanced activation of the Nrf2/HO-1 pathway. These findings indicate that the suppression of the Nrf2/HO-1 pathway partially mitigated the anti-inflammatory and antioxidative effects of RES, along with its ability to enhance cognitive/learning functions in PSD rats. In contrast, activators of the Nrf2/HO-1 pathway amplified these beneficial effects. Thus, the Nrf2/HO-1 pathway may be pivotal in mediating the therapeutic benefits of RES against oxidative stress, inflammation, as well as cognitive impairment in PSD rats (Bai et al., 2024).

Trans-resveratrol (Trans-RES) is the main active ingredient in R. japonica Houtt. and is also found in dietary sources such as grapes and red wine (Bai et al., 2010). It has antioxidant, anti-inflammatory, and neuroprotective properties and has been shown to improve learning and memory impairments (Chen et al., 2007; Ranney and Petro, 2009). Cerebral ischemia affects the neuroendocrine system by activating the HPA axis, resulting in behavioral problems. Studies have demonstrated that an increased adrenal weight-to-body weight ratio is associated with adrenal hyperplasia in MCAO rats. In addition, corticotropin-releasing factor expression was elevated in the frontal cortex, hippocampus, and hypothalamus of MCAO rats. High doses of trans-RES significantly mitigated these changes, suggesting an overall improvement in neuroendocrine function. Moreover, trans-RES enhanced BDNF expression in the frontal cortex, hippocampus, and hypothalamus of MCAO rats, indicating its potential neuroprotective role in ischemic injury. These findings highlight trans-RES’s mechanism of action at the psycho-neuroendocrine level, particularly as a modulator of the HPA axis (Pang et al., 2015).

Inulin is a natural intestinal regulator that balances GM, corrects endocrine dysfunction, and enhances immune responses (Vandeputte et al., 2017; Wan et al., 2020). Its consumption promotes the proliferation of beneficial gut bacteria, which are linked to the production of insulin-like growth factor 1 (IGF-1), an endocrine hormone that reduces body weight by regulating fatty acid synthesis and lipid metabolism (Birkeland et al., 2020; Le Bastard et al., 2020). Inulin crosses the BBB and influences neuronal development, proliferation, and differentiation via the MAPK signaling pathway (Yang et al., 2021). In PSD rats, inulin consumption significantly enhanced MAPK signaling in the hippocampus and altered GM composition, increasing Lactobacillus and Clostridium populations while reducing body weight. Additionally, inulin supplementation elevated IGF-1 levels in the bloodstream, activating the MAPK pathway and alleviating depression-like behaviors in PSD rats (Shao et al., 2024) (Figure 5).