Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: May 11, 2023

In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up 27% patients with MDD associated more severe, chronic, treatment-resistant trajectory. Inflammation not unique depression has transdiagnostic effects suggesting shared underlying psychopathologies metabolic disorders. Research supports association but necessarily causation Putative mechanisms link dysregulation the HPA axis immune cell glucocorticoid resistance resulting in hyperactivation peripheral system. The extracellular release DAMPs DAMP-PRR signaling creates feed forward loop that accelerates central inflammation. Higher plasma levels inflammatory cytokines, most consistently interleukin IL-1β, IL-6, TNF-α, are correlated greater depressive symptomatology. Cytokines sensitize axis, disrupt negative feedback loop, further propagate reactions. Peripheral inflammation exacerbates (neuroinflammation) through several including disruption blood-brain barrier, cellular trafficking, activation glial cells. Activated cells chemokines, reactive oxygen nitrogen species into extra-synaptic space dysregulating neurotransmitter systems, imbalancing excitatory inhibitory ratio, disrupting neural circuitry plasticity adaptation. particular, microglial toxicity plays role pathophysiology neuroinflammation. Magnetic resonance imaging (MRI) studies show reduced hippocampal volumes. Neural dysfunction such as hypoactivation between ventral striatum ventromedial prefrontal cortex underlies melancholic phenotype Chronic administration monoamine-based antidepressants counters response, delayed therapeutic onset. Therapeutics targeting mediated immunity, generalized specific pathways, nitro-oxidative have enormous potential advance treatment landscape. Future clinical trials will need include system perturbations biomarker outcome measures facilitate novel antidepressant development. this overview, we explore correlates elucidate pathomechanisms development biomarkers therapeutics.

Language: Английский

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The chronic unpredictable mild stress (CUMS) Paradigm: Bridging the gap in depression research from bench to bedside

Brain Research, Journal Year: 2024, Volume and Issue: 1843, P. 149123 - 149123

Published: Nov. 1, 2024

Language: Английский

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Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(6), P. 1727 - 1727

Published: March 17, 2024

Major Depressive Disorder (MDD) is one of the most disabling diseases in world. MDD traditionally diagnosed based on a patient’s symptoms, which can lead to misdiagnosis. Although pathogenic mechanisms are unknown, several studies have identified mitochondrial dysfunction as central factor onset and progression MDD. In context MDD, alterations metabolism imbalances energy production oxidative stress, contributing disorder´s underlying pathophysiological mechanisms. Consequently, identification key biomarker for early accurate diagnosis represents significant challenge. Faced with limits traditional treatments antidepressants, new pharmacological therapeutic targets being investigated such ketamine/esketamine, psychedelics, or anti-inflammatories. All these drugs show potential antidepressant effects due their speed action ability modulate neuroplasticity and/or motor processing. parallel, non-pharmacological studied, like Transcranial Magnetic Stimulation (TMS) Deep Brain (DBS), recognized neuronal activity offer treatment alternatives. As cellular directly related respiration, aim this review examining link between assessing how biomarkers could provide more objective precise diagnostic tool, exploring other addition specific focus emerging targets. Finally, detailed analysis strengths, weaknesses, opportunities, threats approaches was carried out, highlighting challenges that must be addressed.

Language: Английский

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Flavonols in Action: Targeting Oxidative Stress and Neuroinflammation in Major Depressive Disorder

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 6888 - 6888

Published: April 7, 2023

Major depressive disorder is one of the most common mental illnesses that highly impairs quality life. Pharmacological interventions are mainly focused on altered monoamine neurotransmission, which considered primary event underlying disease's etiology. However, many other neuropathological mechanisms contribute to progression and clinical symptoms have been identified. These include oxidative stress, neuroinflammation, hippocampal atrophy, reduced synaptic plasticity neurogenesis, depletion neurotrophic factors, dysfunction hypothalamic-pituitary-adrenal (HPA) axis. Current therapeutic options often unsatisfactory associated with adverse effects. This review highlights relevant findings concerning role flavonols, a ubiquitous class flavonoids in human diet, as potential antidepressant agents. In general, flavonols be both an effective safe option management depression, largely based their prominent antioxidative anti-inflammatory Moreover, preclinical studies provided evidence they capable restoring neuroendocrine control HPA axis, promoting alleviating depressive-like behavior. Although these promising, still far from being implemented practice. Hence, further needed more comprehensively evaluate respect improvement signs depression.

Language: Английский

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Role of brain renin–angiotensin system in depression: A new perspective

CNS Neuroscience & Therapeutics, Journal Year: 2023, Volume and Issue: 30(4)

Published: Nov. 12, 2023

Abstract Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression related to the deficiency serotonin (5HT), which derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in pathogenesis depression. Notably, renin–angiotensin system (RAS) depression, different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) angiotensin receptor blockers (ARBs) may be effective However, underlying mechanism for role dysregulated brain RAS‐induced remains speculative. Therefore, this review aimed revise conceivable ACEIs ARBs how these agents ameliorate Dysregulation RAS triggers development progression through reduction 5HT expression brain‐derived neurotrophic factor (BDNF) induction mitochondrial neuroinflammation. inhibition central classical ARBS activation non‐classical prevent regulating 5HT, BDNF,

Language: Английский

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Kaempferol Improves Breast Cancer-Related Depression through the COX-2/PGE2 Pathway

Frontiers in Bioscience-Landmark, Journal Year: 2023, Volume and Issue: 28(11), P. 311 - 311

Published: Nov. 28, 2023

Background: Breast cancer-related depression (BCRD) is strongly associated with BC and increases recurrence mortality. This study investigated the role of kaempferol in pathogenesis BCRD its underlying mechanism. Methods: 4T1 mouse cells were treated corticosterone (Cort) vitro to develop a neuronal injury model, model was established by injecting Cort. The effects on models measured behavioral tests, Cell Counting Kit-8 assay, wound healing colony formation Western blot analysis, quantitative real-time PCR, hematoxylin eosin staining, enzyme-linked immunosorbent immunofluorescence. transfected cyclo-oxygenase-2 (COX-2) overexpression plasmid COX-2/prostaglandin E2 (PGE2) axis anti-BCRD activity kaempferol. connection between COX-2 analyzed molecular docking. Results: Kaempferol reduced viability, migration, clones inhibited growth depression-like behavior mice. alleviated inflammation BCRD, decreased interleukin 1 beta (IL-1β) IL-6 levels, increased transforming factor (TGF-β1) IL-10 levels. In addition, elevated levels serotonin, dopamine, norepinephrine amount 5-Bromo-2′-deoxyuridine/neuronal nuclei-positive cells. downregulated PGE2, could dock protein structure COX-2. Overexpression upregulated IL-1β TGF-β1 expression. reversed protective Conclusion: exerted effects, at least part inhibiting COX-2/PGE2 pathway, which regulates neuroinflammation, neurotransmitter imbalance, defective neurogenesis. Therefore, may be promising candidate active ingredient for treating BCRD.

Language: Английский

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Bambusa vulgaris Extract: A Potential Natural Biogenic Amine Neurotransmitters Modulator, COX-2 Inhibitor and Oxidative Species Suppressor for Managing Depression and Anxiety

Natural Product Communications, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 1, 2025

Objective Literature reveals a significant deficiency in scientific investigations regarding the use of Bambusa vulgaris extract (BVE) for treatment neuropsychiatric disorders, particularly those characterized by anxiety and depression. Thus, this study was designed to examine anxiolytic antidepressant-like properties BVE using mouse models, while also elucidating potential underlying mechanisms responsible observed antidepressant effects extract. Methods Validated behavioral assessments were employed assess (including hole-board test (HBT), open field (OFT), elevated plus maze (EPMT), light/dark exploration (LDET)) as well (comprising forced swim (FST) tail suspension (TST)) Chronic mild stress paradigms induce depressive-like behaviors subjects. The mice administered treatments consisting distilled water (10 mL/kg; serving negative control), fluoxetine (20 mg/kg; standard drug), (at varying doses 100, 200, 400 mg/kg). concentrations biogenic amine neurotransmitters (noradrenaline serotonin) cyclooxygenase-2 (COX-2) within brain measured ELISA kits. Antioxidant biomarkers assessed through application standardized commercial assay Results significantly diminished levels subjects, demonstrated an enhancement exploratory activities light/open enclosures increased aversion darker compartments. Furthermore, alleviated depression-like mice, which reflected latency immobility reduction overall duration immobility. enhanced noradrenaline serotonin neurotransmission, suppressed oxidative species, inhibited COX-2 activity. Conclusion results obtained from suggest that demonstrates properties, latter being mediated serotonin), inhibition activity, suppression radicals brain.

Language: Английский

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BDNF/BDNF-AS Gene Polymorphisms Modulate Treatment Response and Remission in Bipolar Disorder: A Randomized Clinical Trial

Journal of Personalized Medicine, Journal Year: 2025, Volume and Issue: 15(2), P. 62 - 62

Published: Feb. 7, 2025

Background: Bipolar disorder (BD) is a chronic condition associated with treatment resistance, cognitive decline, structural brain changes, and an approximately 13-year reduction in life expectancy compared to the general population. Depression BD substantially impairs quality of life, while neuroinflammation excitotoxicity are thought contribute recurrence mood episodes disease progression. Brain-derived neurotrophic factor (BDNF) plays key role neuronal growth function, its dysregulation being linked various psychiatric disorders. This study extension previously published clinical trial was conducted assess effects three BDNF BDNF-AS gene polymorphisms (rs1519480, rs6265, rs10835210) on outcomes serum levels patients treatment-resistant bipolar depression (TRBDD) over eight-week period. Methods: included 41 participants from randomized trial, all whom had available samples genotype data. The participants, aged 21 65, were diagnosed disorder, assessed using Maudsley Staging Method. Participants randomly assigned receive either escitalopram plus placebo (ESC+PBO) or celecoxib (ESC+CBX) 8-week Statistical analyses mixed ANOVA chi-square tests compare minor allele carrier status SNPs response remission rates. Results: Non-carriers rs6265 A (p = 0.005) carriers rs10835210 0.007) showed significantly higher adjunctive alone. Additionally, rates after both non-carriers across However, notably rs1519480 G allele, as well allele. Conclusions: suggests that genetic variations genes influence disorder.

Language: Английский

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Substituted aryl piperazine ligands as new dual 5-hLOX/COX-2 inhibitors. Synthesis, biological and computational studies

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108398 - 108398

Published: March 1, 2025

Language: Английский

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Neuroinflammation—A Crucial Factor in the Pathophysiology of Depression—A Comprehensive Review

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 502 - 502

Published: March 30, 2025

Depression is a multifactorial psychiatric condition with complex pathophysiology, increasingly linked to neuroinflammatory processes. The present review explores the role of neuroinflammation in depression, focusing on glial cell activation, cytokine signaling, blood-brain barrier dysfunction, and disruptions neurotransmitter systems. article highlights how inflammatory mediators influence brain regions implicated mood regulation, such as hippocampus, amygdala, prefrontal cortex. further discusses involvement hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, kynurenine pathway, providing mechanistic insights into chronic inflammation may underlie emotional cognitive symptoms depression. bidirectional relationship between depressive emphasized, along peripheral immune responses systemic stress. By integrating molecular, cellular, neuroendocrine perspectives, this supports growing field immunopsychiatry lays foundation for novel diagnostic biomarkers anti-inflammatory treatment approaches Further research holds promise developing more effective personalized interventions individuals suffering from

Language: Английский

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