The neurobiological mechanisms and therapeutic prospect of extracellular ATP in depression

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(2)

Published: Feb. 1, 2024

Depression is a prevalent psychiatric disorder with high long-term morbidities, recurrences, and mortalities. Despite extensive research efforts spanning decades, the cellular molecular mechanisms of depression remain largely unknown. What's more, about one third patients do not have effective anti-depressant therapies, so there an urgent need to uncover more guide development novel therapeutic strategies. Adenosine triphosphate (ATP) plays important role in maintaining ion gradients essential for neuronal activities, as well transport release neurotransmitters. Additionally, ATP could also participate signaling pathways following activation postsynaptic receptors. By searching website PubMed articles "ATP depression" especially focusing on extracellular (eATP) last 5 years, we found that numerous studies implied insufficient from astrocytes lead exogenous supply eATP or endogenously stimulating alleviate depression, highlighting potential alleviating depression.

Language: Английский

---

Identification of blood transcriptome modules associated with suicidal ideation in patients with major depressive disorder

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 7, 2025

The risk of suicide in patients with major depressive disorder (MDD) poses a concern, studies suggesting that genetics may be contributing factor. Although there are many transcriptomic on postmortem brain tissue related to suicidal behavior, the blood transcriptional mechanisms ideation (SI) remain unknown. This study utilized weighted gene coexpression network analysis (WGCNA) approach investigate associations between modules and SI individuals MDD using peripheral RNA-seq data from 75 (MDD_SI), 82 without (MDD_nSI), 149 healthy controls (HC). An ANCOVA was conducted assess differences among groups, age sex included as covariates. ontology (GO) Kyoto encyclopedia genes genomes (KEGG) databases were used annotate module functions. Results indicated magenta (associated RNA splicing processes) differentiated MDD_SI MDD_nSI (p = 0.021), while green (related immune inflammatory responses) distinguished HC 0.004). Additionally, three showed HC: 0.009), brown innate immunity mitochondrial metabolism; p 0.001), turquoise energy metabolism neurodegeneration; 0.005). Our findings highlight expression regulation, response, inflammation linked MDD, pathways associated immunity, metabolism, function, neurodegeneration appear more broadly MDD.

Language: Английский

---

From energy metabolism to mood regulation: The rise of lactate as a therapeutic target

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Disruption of cerebral energy metabolism is increasingly recognized as a key factor in the pathophysiology mood disorders. Lactate, beyond its role metabolic byproduct, now understood to be critical player brain homeostasis and modulator neuronal function. Recent advances understanding lactate shuttling between astrocytes neurons have opened new avenues for exploring multifaceted roles regulation. Exercise, known modulate levels, further underscores potential therapeutic target This review delves into alterations associated with disorders, emphasizing their implications dynamics signaling pathways. Additionally, we discuss particularly through capacity remodel We conclude by assessing promise exercise-induced production novel strategy disorder treatment. Alterations may contribute pathogenesis In several studies, not only substrate metabolism, but also molecule that triggers cascades. Specifically, involved regulation neurogenesis, neuroplasticity, endothelial cell function, microglia lysosomal acidification, therefore improving Meanwhile, exercise low-risk intervention can improve disorders Thus, evidence from this supports could disorder, contributing deeper intervention.

Language: Английский

---

Regional Gene Expression Patterns are Associated with Functional Connectivity Alterations in Major Depressive Disorder with Anxiety Symptoms

ALPHA PSYCHIATRY, Journal Year: 2025, Volume and Issue: 26(2)

Published: April 21, 2025

Background: Understanding gene expression and functional connectivity (FC) changes in depressed patients with anxiety can help develop personalized therapies. Herein we examine the link between transcriptome data FC differences major depressive disorder significant (MDD/ANX+) without (MDD/ANX-). Methods: We compared MDD/ANX+ group (n = 294) MDD/ANX- 218) to identify at both edge-based network levels. Using Allen Human Brain Atlas, performed partial least squares regression analysis genes associated observed disparities, followed by a enrichment analysis. Results: The results from network-level analyses consistently indicated significantly increased subcortical (SC) visual network, as well SC dorsal attention group. Additionally, transcriptome-neuroimaging correlation revealed that of 1066 was spatially correlated groups. These were enriched translation synapses adenosine triphosphate (ATP) generation. Conclusions: Our indicate variations synaptic ATP generation may affect risk MDD patients.

Language: Английский

---

Demethylase FTO Regulates P2X3R Expression Contributing to the Mechanism of Hyperalgesia in Lumbar Disc Herniation

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(4)

Published: April 1, 2025

Lumbar disc herniation (LDH) is a common chronic orthopedic condition characterized by the protrusion of nucleus pulposus tissue, leading to low back and leg pain. Its pathophysiology remains poorly understood. The aim this study was investigate whether demethylase Fat mass obesity-associated protein (FTO) mediates local translation P2X3 receptors (P2X3R) in rat model LDH. effect process on excitability dorsal root ganglion (DRG) cells also examined, which may elucidate peripheral molecular mechanisms underlying specific pain sensitivity LDH models were established male Sprague-Dawley rats. Behavioral tests assessed mechanical thermal thresholds motor function. expression P2X3R FTO DRG investigated RT-qPCR, Western blot, immunofluorescence. knocked down, methylation examined MeRIP validate their roles. IL-1β IL-6 levels quantified ELISA. Protein interactions predicted using AutoDock, neuronal patch clamp recordings. Compared with Sham group, group showed reduction threshold hind limbs. There no significant differences increased group. DRG, localized mainly cell membrane colocalized NeuN. Intrathecal injection P2X3R-siRNA FTO-siRNA effective increasing thresholds, reducing FTO, decreasing neurons, IL-6. RNA Methylation Immunoprecipitation (MeRIP) analysis revealed reduced m6A modification mRNA AutoDock hydrogen bond between P2X3R. These findings suggest that regulates DRG. This influences contributes LDH-induced hyperalgesia.

Language: Английский

---

Neural energy coding patterns of dopaminergic neural microcircuit and its impairment in major depressive disorder: A computational study

PLoS Computational Biology, Journal Year: 2025, Volume and Issue: 21(4), P. e1012961 - e1012961

Published: April 7, 2025

Numerous experiments have found that the behavioral characteristics of major depressive disorder (MDD) animals are usually associated with abnormal neural activity patterns and brain energy metabolism. However, relationship among characteristics, metabolism remains unknown. In this paper, we computationally investigated relationship, especially studied how coding changed in MDD brains, VTA-NAc-mPFC dopaminergic pathway reward system based on our biological network model calculation model. Interestingly, results suggested consumption whole microcircuit group was significantly reduced, which mainly attributed to decreasing mPFC region. This observation theoretically supported view low-level MDD. We also various neuronal types under influence different dopamine concentrations, there were some specific impairments MDD, provided potential biomarkers for diagnosis. More specifically, actual medium spiny neurons (MSNs) NAc region increased group, whereas pyramidal exhibited higher NC group. Additionally, both neuron types, required generate an action suggesting that, given same budget, these tended fewer potentials. To further explore between microcircuit, addition calculated P-V correlation each defined as Pearson’s coefficient membrane power. The showed power not perfectly correlated (P-V correlations ranged from 0.6 0.9), concentration inputs affected MSN, CB interneurons It joint application theory will be superior any single theory, could help discovery new mechanisms neurocircuits Overall, study only uncovered but presented a novel pipeline theory.

Language: Английский

---

Restoration of mitochondrial energy metabolism by electroconvulsive therapy in adolescent and juvenile mice

Frontiers in Psychiatry, Journal Year: 2025, Volume and Issue: 16

Published: April 10, 2025

Adolescent depression is an increasingly serious public health issue, and traditional treatment methods often have side effects or limited efficacy. Electroconvulsive therapy (ECT), a widely used for severe depression, has recently gained attention its potential in treating adolescent depression. Previous studies suggest that mitochondrial dysfunction closely related to the onset of Therefore, investigating mechanism by which ECT alleviates depressive symptoms through improvement energy metabolism great significance. This study employed chronic unpredictable mild stress (CUMS) mouse model assess on depression-like behaviors sucrose preference test, open field tail suspension test. Additionally, markers, including ATP levels, oxygen consumption rate (OCR), lactate, pyruvate, were measured both human plasma evaluate function. The results showed significantly improved anxiety-like mice, as evidenced reversal abnormal Analysis markers revealed increased restored OCR, reduced lactate accumulation, pyruvate levels. These findings restoring improving brain supply. systematically explored metabolism. indicate not only effectively but also provides new insights experimental evidence function restoration. Future research could further investigate how combine drug treatments enhance function, improve efficacy, different subtypes, providing guidance personalized clinical treatment.

Language: Английский

---

Brexpiprazole augmentation and mitochondrial gene expression changes in major depressive disorder

Journal of Psychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Background: Overall, 20% of patients with major depressive disorder (MDD) are treatment-resistant and do not respond to multiple antidepressant monotherapies. For such patients, augmentation therapy antipsychotics is one the therapeutic options. However, mechanism essentially unknown. Aim: This study aimed elucidate brexpiprazole (BREX) at gene expression levels. Methods: Vehicle, escitalopram (ES), BREX, ES + BREX (augmentation therapy) were administered mouse neuroblastoma (Neuro2a) cells submitted RNA-sequencing. Gene expressions also measured in whole blood MDD frontal cortices hippocampi mice after treatment for 20 days. Results: On RNA-seq ontology analyses, upregulation mitochondria (MT)-related genes was confirmed by quantitative Polymerase Chain Reaction (PCR). These upregulated successfully validated both Neuro2a Caco2 cells. Decreased MT-ATP8 found patients. Furthermore, changes MT-mRNA therapy. Conclusions: modified vitro vivo experiments. may be a key finding improving our understanding pathogenesis clinical practice.

Language: Английский

---