Chronic mental stress and ischemic injury: Mechanisms and implications – A mini review

Abstract

Ischemic stroke is a leading cause of mortality and disability worldwide. Emerging evidence has highlighted a strong link between genetically predisposed risk factors, such as depression and chronic mental stress, and worsens stroke outcomes. This mini review explores the multifaceted role of mental stress in exacerbating ischemic injury. We discuss mechanisms at the cellular, subcellular, and epigenetic levels, including differential brain cell sensitivity, mitochondrial dysfunction, and novel epigenetic modifications like lactylation. This review provides a theoretical framework and scientific basis for understanding the clinical implications of mental stress in ischemic stroke management. The findings underscore the importance of further research to clarify these mechanisms and develop targeted interventions to mitigate the adverse effects of mental stress on stroke outcomes.

Introduction

Cerebrovascular diseases (CVD) include pathological conditions that disrupt blood flow and impair brain vasculature.[1,2] Among these, ischemic stroke stands as the most severe and debilitating, significantly burdening patients and their families. Traditional risk factors for CVD, including genetic predisposition, hyperlipidemia, hypertension, and hyperglycemia have been well documented.[3] Alarmingly, ischemic strokes have been occurring at younger ages, with studies from 2010 to 2018 showing a significant increase in stroke incidence among individuals under 55 years old, compared to earlier data (2002–2010).[4]

While traditional risk factors such as hypertension, diabetes, and hyperlipidemia have declined among young stroke patients, mental stress has emerged as an underrecognized but critical factor, particularly among younger populations.[5,6] This review emphasizes the role of mental stress in stroke physiopathology and its potential to worsen outcomes, providing both theoretical and clinical insights for stroke prevention and treatment, especially in younger individuals.

Mental stress is defined as the disruption of homeostasis caused by internal or external factors, such as social stress and psychological burdens.[7] Mental stress significantly contributes to the pathophysiology of mental illnesses, including anxiety and depression.[8,9] The 2019 China Mental Health Survey reported a lifetime prevalence of mental illnesses of approximately 16.6%. Mental stress not only induces depressive behaviors but also contributes to physical diseases.[10,11] Psychosomatic illnesses, increasingly recognized in the literature, show growing evidence linking mental stress to cardiovascular events. For example, a JAMA report indicated that mental stress elevates cardiovascular risks in patients with stable coronary heart disease.[12]

Mendelian randomization studies analyzing genetic variants associated with depression have shown their impact on stroke prognosis, exacerbating outcomes in stroke patients within 90 days postonset.[13] Furthermore, chronic stress (e.g., 28-day exposure involving predator scent, restraint, and tail suspension stress) has been demonstrated to increase lesion volume in mice undergoing middle cerebral artery occlusion, implicating endothelial mechanisms in stress-aggravated stroke outcomes.[14] However, the exact relationship between mental stress and stroke outcomes remains unclear, necessitating further investigation. This review delves into the mechanisms by which mental stress exacerbates stroke outcomes, including those at the level of brain cells, subcellular organelles, and epigenetic modifications [Figure 1].

Figure 1.

The potential mechanism of mental stress aggravating stroke damages

Cellular Mechanisms Underlying Stress-induced Pathology

The brain’s primary cell types – neurons and glial cells (microglia, astroglia, and oligodendrocytes) – are all influenced by mental stress, potentially affecting stroke prognosis.

Neurons

Neurons are particularly vulnerable to mitochondrial damage under mental stress due to their high sensitivity to ischemia-reperfusion (I/R) injury. Dysfunctional mitochondria within neurons struggle to generate sufficient adenosine triphosphate (ATP), impairing the repair of reversible injury in the ischemic penumbra and exacerbating I/R damage. This leads to elevated reactive oxygen species (ROS) levels, worsening stroke injury. In addition, neurons may adapt to microenvironmental changes by reducing the number of synapses, a process that consumes considerable energy.[15]

Mitochondrial dysfunction in neuron is triggered by I/R, and mental stress can further induce mitochondrial dysfunction. This dysfunction impairs the mitochondria’s ability to generate adequate ATP for repairing neurons within the ischemic penumbra, leading to more severe stroke injury.[16,17] Thus, mitochondrial dysfunction plays a central role in the aggravation of stroke outcomes by mental stress, although the precise causal relationship remains unclear.

Glial cells – Microglia

Microglia, the brain’s primary immune cells, play a crucial role in regulating neuroinflammation in both healthy and diseased brains. Mental stress has been shown to activate microglia and trigger neuroinflammation.[18,19] For instance, the expression of the ionized calcium-binding adaptor molecule 1 (IBA1), microglial marker, is significantly upregulated in individuals with depression,[20] and its density is elevated in the dorsal prefrontal white matter of those with psychiatric disorders.[21] In animal models, stress activates microglia in the ventral dentate gyrus (DG) of the hippocampus and astrocytes in both the dorsal and ventral DG.[22] Anti-inflammatory agents like catalpol have demonstrated efficacy in alleviating depressive-like behaviors in mice exposed to chronic, unpredictable mild stress by inhibiting the polarization of microglia to the pro-inflammatory M1 phenotype.[23] Similarly, Saikosaponin B2, a treatment for depression, has been shown to mitigate depressive-like behaviors in chronic stressed mice by reducing neuroinflammation and microglial activation through the TLR4/NF-κB pathway.[24] These findings underscore the strong association between mental stress, microglial activation, and neuroinflammation, emphasizing the therapeutic potential of anti-inflammatory therapies.

As the brain’s primary responders to pathophysiological changes, microglia are pivotal in ischemic stroke, where they mediate the inflammatory response.[25] Targeted modulation of microglial activation, such as through the downregulation of PARP14 expression, has been shown to improve functional recovery after stroke.[26] In addition, cottonseed oil has been found to alleviate ischemic stroke injuries by reducing the activation of microglia and astrocytes, with the TLR4/NF-κB pathway identified as a critical mediator.[26] Recent evidence also highlights the dual role of microglial activation in stroke recovery, as it facilitates neurogenesis, angiogenesis, and synaptic remodeling.[25,27] These findings suggest that mental stress, through its impact on microglial activation, may exacerbate stroke outcomes. However, further research is needed to fully elucidate the complex interactions between metal stress, microglial activation, and stroke recovery.

Glial Cells – Astrocytes

Astrocytes, the most abundant cells in the brain, play a pivotal role in the response to psychological stress, making them a growing focus of research. These cells actively regulate stress responses through various receptors and enzymes. For instance, stress hormones have been shown to upregulate the expression of the phagocytic receptor Mer Tyrosine Kinase in astrocytes through the glucocorticoid receptor (GR), a response not observed in microglia.[28] The GR in astrocytes is closely linked to stress vulnerability; its absence induces depressive-like behaviors, while increased GR expression in the medial prefrontal cortex prevents the onset of depressive-like phenotypes.[29] Similarly, O-GlcNAc transferase (OGT) has been implicated in mood regulation, as deleting OGT in astrocytes produces antidepressant-like effects.[30] These findings highlight the critical involvement of astrocytes in modulating stress-induced psychological changes.

Astrocytes also play a central role in vascular repair and remodeling following ischemic stroke. Removing a subset of reactive astrocytes after a stroke has been shown to impair vascular and extracellular matrix remodeling, leading to prolonged deficits in blood flow, increased vascular permeability, continued cell death, and worsened motor recovery.[31]

Glial cells – Oligodendrocytes

Oligodendrocytes, the myelinating cells of the central nervous system, represent 5%–10% of the total glial population. Despite their relatively small proportion, these cells play a pivotal role in stress-induced depressive-like behaviors. Research has linked decreased myelination to depression, while ketamine – an antidepressant – has been shown to promote the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes, restoring impaired myelination and alleviating depressive symptoms.[32]

A study published in cell highlighted that a purine metabolic disorder in CD4+ T-cells may contribute to stress-driven anxiety-like behaviors, identifying oligodendrocytes in the left amygdala as key targets of CD4+ T-cell-derived xanthine.[33] Beyond mental health, OPCs also aid functional recovery following ischemic stroke.[34] Notably, engrafted OPCs have been shown to enhance endogenous oligodendrogenesis, neurite growth, and synaptogenesis, thereby promoting recovery after ischemic stroke.[35] These findings suggest oligodendrocytes may represent a critical mechanism linking mental stress to worsened stroke outcomes.

Subcellular Organelles Affected by Mental Stress

Subcellular organelles such as mitochondria, the endoplasmic reticulum (ER), and lysosomes are particularly vulnerable to mental stress, which can exacerbate poststroke injuries. Chronic stress imposes sustained energy demand on cells, with mitochondria playing a central role in stress-related disorders.[36]

Mitochondria

Mitochondria are essential for cellular energy production through oxidative phosphorylation and act as critical mediators in stress adaptation. Increasing evidence indicates a strong association between mental stress and mitochondrial dysfunction. Mitochondria sense metabolic stress and undergo dynamic morphological and functional changes to meet energy demands and restore homeostasis (allostasis).[37,38] However, prolonged stress-induced energy demands can overwhelm mitochondria, leading to dysfunction. This disruption has been linked to behavioral changes and neurological.[39]

A review of 23 studies examining stress-related mitochondrial changes reported compromised mitochondrial membrane potential, ATP synthesis, and increased ROS production in nearly half of the studies.[40] In the context of cerebral I/R injury, healthy mitochondria facilitate neuronal repair and improve outcomes by maintaining energy supply in the ischemic penumbra regions surrounding the infarct where neurons remain structurally intact but functionally impaired.[41,42] These insights underscore mitochondrial dysfunction as a key link between mental stress and stroke outcomes.

Endoplasmic reticulum

The ER, a key organelle responsible for protein synthesis and transport, is highly sensitive to mental stress. Stress-induced dysfunction of the ER, known as ER stress (ERS), has been closely associated with the development of mental disorders, particularly through its effects on GABAergic neurons in the basolateral amygdala.[43] ERS also plays a role in stress-related damage to mesencephalic dopaminergic neurons,[44] further highlighting its involvement in neural injury.

ERS triggers the unfolded protein response (UPR), a protective mechanism aimed at restoring cellular homeostasis. Among the UPR pathways, activating transcription factor 6 is a key mediator of the stress response.[45] In addition, ERS has been shown to influence the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling pathway, which is critical for neuronal survival and plasticity. Alterations in this pathway have been implicated in worsened outcomes following stroke.[46]

These findings underscore the ER as a crucial link between mental stress and adverse cerebrovascular outcomes, particularly in the context of I/R injuries. Addressing ER dysfunction may represent a promising therapeutic approach for mitigating the impact of stress on neurological health.

Lysosomes

Lysosomes play a pivotal role in maintaining cellular homeostasis by facilitating protein degradation and recycling. Dysfunction in autophagy, a process heavily reliant on lysosomal activity, has been implicated in the pathogenesis of various psychiatric disorders. Notably, mental stress has been shown to enhance secretory autophagy through the action of the stress-responsive co-chaperone FK506-binding protein 51.[47]

The autophagy-lysosomal pathway (ALP), regulated by transcription factor EB (TFEB), has demonstrated protective effects against cerebral ischemic damage. TFEB’s ability to enhance autophagic flux and lysosomal biogenesis positions it as a promising therapeutic target for neuroprotection in ischemia.[48]

These findings suggest that lysosome-mediated autophagy serves as a critical mechanism connecting mental stress to stroke-related injuries. Future research into ALP modulation may unlock new avenues for therapeutic interventions aimed at mitigating the neurological impacts of mental stress.

Epigenetic Modifications in Stress

Mental stress is strongly linked to epigenetic alterations in genes that mediate resilience and vulnerability to stress. These modifications, which include histone modifications and DNA methylation (DNAm),[49] play critical roles in stress responses and associated health outcomes.

Histone modification: Lactylation

Chronic mental stress increased lactate levels in skeletal muscles and peripheral blood,[50] while acute mental stress activates the brain’s central motor circuit, altering leukocyte distribution in peripheral blood.[51] Lactic acid, a small lipid molecule, crosses the blood–brain barrier (BBB) to reach energy-demanding brain regions.[52]

Lactylation, a novel post-translational modification,[53] occurs when lactic acid acts as a precursor for histone lysine residue modification through the p300/cAMP responsive element binding protein (CBP) enzyme. This modification relaxes chromatin structure, enhancing gene transcription. Elevated histone lactylation has been linked to homeostasis-related genes, such as arginase 1, which supports wound healing during the late polarization of M1 macrophages.[53]

In brain cells, lysine lactylation (Kla) was increased significantly during acute social defeat stress and neural excitation in mice, corresponding to elevated lactate levels.[54] While lactylation appears to play a crucial role in regulating stress-related stroke outcomes, its effects on neuronal mitochondrial function and stroke prognosis warrant further exploration.

Histone modification: Acetylation

Histone acetylation represents another key modification involved in stress responses. Acute restraint stress models have shown increased histone H3 acetylation in the hippocampus, with the histone deacetylase inhibitor, trichostatin A, reversing stress-induced emotional changes.[55]

Interestingly, supplementation with acetyl coenzyme A demonstrates antidepressant-like effects and enhances synaptic plasticity in the hippocampus.[56] Conversely, inhibiting histone acetylation in neurons provides neuroprotection against ischemic stroke,[57] improving long-term neurological outcomes.[58]

DNA methylation

DNAm is widely implicated in mental stress-related psychiatric disorders.[59] For instance, DNA hypermethylation in major depression disorder was validated in a large Chinese cohort (n = 1,346) using the Sequenom Mass ARRAY method, underscoring its potential as a biomarker for depression diagnosis and treatment.[60]

In ischemic stroke, DNA demethylation plays a significant role in determining outcomes. Specifically, exocyst complex component 4 (EXOC4) methylation was negatively correlated with long-term outcomes in stroke patients. Furthermore, in a hyperinflammatory cerebral ischemia mouse model, inhibiting DNAm resulted in poorer functional recovery following stroke.[61]

Brain cells, including neurons, microglia, astrocytes, and oligodendrocytes, are all influenced by mental stress, potentially affecting stroke prognosis. Organelles such as mitochondria, ER, and lysosomes are also impacted. Epigenetic modifications-lactylation, acetylation, and DNAm-mediate stress-induced damage, contributing to brain injury upon stroke.

Conclusion

This review highlights the growing incidence of neuropsychiatric and CVDs, underscoring mental stress as an independent risk factor that exacerbates cerebrovascular conditions. By exploring the cellular and molecular mechanisms linking mental stress to the progression of these diseases, the review provides a foundation for new perspectives and potential therapeutic targets for stress-related cerebrovascular conditions.

The novel concept of lactylation identified as a potential modifier of stress responses, introduces exciting research opportunities. Understanding how mental stress exacerbates stroke outcomes through mechanisms such as subcellular organelle dysfunction, cellular dysfunction, and epigenetic modifications could drive significant advancements in preventive and therapeutic strategies.

Beyond mental stress, other factors influencing poststroke outcomes, such as sepsis and Alzheimer’s disease (AD), also warrant consideration.[62] Sepsis can lead to sepsis-associated encephalopathy, which exacerbates stroke-related cognitive impairment and increases mortality. The underlying mechanisms include BBB disruption, neuroinflammation, immune cell infiltration, and mitochondrial dysfunction. The potential protective role of tissue non-specific alkaline phosphatase in this context has also been highlighted.[63] Similarly, the relationship between ischemic stroke and AD has been elaborated on, emphasizing the role of protein kinase C (PKC) activity. PKC is critical for memory and BBB integrity, and alterations in its activity due to age or disease contribute to neurodegeneration, linking poststroke outcomes to AD pathology.[64]

Future Research Directions

Based on the current literature, several avenues for future research emerge:

Clarifying mechanisms of stress-induced stroke outcomes

The exact mechanisms by which mental stress influences stroke outcomes remain poorly understood. Mitochondrial dysfunction and the cumulative effects of various types of stress on neuronal mitochondrial health are areas requiring further investigation.

Exploring epigenetic modifications

The emerging role of acetylation as an epigenetic modification influencing stress responses and stroke outcomes offers a promising direction. Research into how acetylation affects neuronal function and recovery could reveal novel therapeutic targets.

Developing therapeutic interventions

There is a critical need for interventions aimed at mitigating the effects of mental stress on cerebrovascular outcomes. Strategies could include stress management techniques, cognitive-behavioral therapy, pharmacological treatments, or approaches targeting mitochondrial function and epigenetic modifications.

Conducting large-scale population studies

Large-scale, population-based studies are essential to better understand the relationship between mental stress and CVDs. Such studies could help identify at-risk populations, key risk factors, and potential intervention points.

While significant progress has been made, addressing these gaps will require a multidisciplinary approach that integrates molecular research with clinical strategies. By advancing our understanding of how mental stress interacts with CVDs, future studies hold the potential to improve outcomes and quality of life for patients at the intersection of these conditions.

Author contributions

Yuequan Zhu: Writing and editing the original draft; Leticia Simo: Writing and editing; Xiaokun Geng: Editing; Fengwu Li: Editing; Yuchuan Ding: Instructing and editing.

Ethical policy and institutional review board statement

Not applicable.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study.

Conflicts of interest

Prof. Yuchuan Ding is an Associate Editor-in-Chief, Prof. Xiaokun Geng is the Executive Editor-in-Chief of Brain Circulation. The article was subject to the journal’s standard procedures, with peer review handled independently of them and their research groups.

Funding Statement

This work was partially supported by the National Natural Science Foundation of China (grant numbers 82301570 and 82271332), the Science Foundation of Capital Medical University (grant number PYZ22181), and the Beijing Tongzhou District Financial Fund (2024).