Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: Feb. 7, 2022

The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory neuroprotective properties. However, its role potential molecular mechanisms in depression remain unclear. present study aimed to investigate antidepressant activity EDA underlying mechanisms.A chronic social defeat (CSDS) model was performed explore whether could produce effects. Behaviors tests were carried out examine depressive, anxiety-like cognitive behaviors interaction (SI) test, sucrose preference test (SPT), open field (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension (TST) forced swim (FST). Hippocampal medial prefrontal cortex (mPFC) tissues collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement MDA, SOD, GSH, GSH-PX, T-AOC transmission electron microscopy (TEM). Western blotting (WB) quantitative real-time polymerase chain reaction (qRT-PCR) detected Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, Sirt1 inhibitor ML385, Nrf2 injected intraperitoneally 30 min before injection daily. Knockdown experiments determine effects Gpx4 on CSDS mice with treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)-EGFP infusion.The administrated dramatically ameliorated CSDS-induced depressive behaviors. In addition, notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, damage, metabolism pro-inflammatory cytokines activation hippocampus (Hip) mPFC mice. Further examination indicated that application after significantly increased protein expressions Sirt1, Nrf2, HO-1 Hip. EX527 abolished effect as well levels Gpx4. Similarly, ML385 reversed anxiolytic via decreased knockdown EDA-generated efficacy behaviors.These findings suggest possesses potent properties through axis Gpx4-mediated ferroptosis may play key this effect.

Language: Английский

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Major depressive disorder: hypothesis, mechanism, prevention and treatment

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 9, 2024

Abstract Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, pathological mechanisms MDD underlying effects pharmacological treatments for are complex unclear, additional diagnostic therapeutic strategies still needed. The currently widely accepted theories pathogenesis include neurotransmitter receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis cytokine neuroplasticity hypothesis systemic influence but these cannot completely explain mechanism MDD. Even it hard to adopt only one reveal MDD, thus recent years, great progress has been made elucidating roles multiple organ interactions identifying novel approaches multitarget modulatory strategies, further revealing disease features Furthermore, some newly discovered potential targets studied antidepressants have attracted widespread attention, reagents even approved clinical treatment methods such as phototherapy acupuncture effective improvement symptoms. In this work, we comprehensively summarize latest research on diagnosis preventive medicines, well related trials.

Language: Английский

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Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome

Annual Review of Psychology, Journal Year: 2019, Volume and Issue: 71(1), P. 49 - 78

Published: Sept. 30, 2019

Depression remains one of the most prevalent psychiatric disorders, with many patients not responding adequately to available treatments. Chronic or early-life stress is key risk factors for depression. In addition, a growing body data implicates chronic inflammation as major player in depression pathogenesis. More recently, gut microbiota has emerged an important regulator brain and behavior also been linked However, how this holy trinity interact maintain physiological homeostasis fully understood. review, we integrate from animal human studies on these three etiology progression We focus processes by which microbiota-immune-stress matrix may influence centrally mediated events possible therapeutic interventions correct imbalances triune.

Language: Английский

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Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

Neuron, Journal Year: 2018, Volume and Issue: 100(3), P. 551 - 563.e7

Published: Sept. 13, 2018

Language: Английский

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Microglia in depression: current perspectives

Science China Life Sciences, Journal Year: 2020, Volume and Issue: 64(6), P. 911 - 925

Published: Oct. 14, 2020

Language: Английский

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Maternal Inflammation and Neurodevelopmental Programming: A Review of Preclinical Outcomes and Implications for Translational Psychiatry

Biological Psychiatry, Journal Year: 2018, Volume and Issue: 85(2), P. 107 - 121

Published: Aug. 27, 2018

Language: Английский

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Brain NMDA Receptors in Schizophrenia and Depression

Biomolecules, Journal Year: 2020, Volume and Issue: 10(6), P. 947 - 947

Published: June 23, 2020

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals humans. However, has recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage conditions is similar, positive symptoms schizophrenia appear before antidepressant effects emerge. Here, we describe temporal mechanisms implicated schizophrenia-like antidepressant-like NMDA blockade rats, postulate that may indicate induce similar mechanistic effects, only basal pre-drug state organism delimitates overall outcome. Hence, receptors depressive-like status can lead to amelioration or remission symptoms, whereas healthy individuals develop psychotic patients show an exacerbation these after administration antagonists.

Language: Английский

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Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(10), P. 1203 - 1203

Published: Sept. 28, 2022

Major depressive disorder (MDD) is a common and complex mental disorder, that adversely impacts an individual’s quality of life, but its diagnosis treatment are not accurately executed symptom-based approach utilized in most cases, due to the lack precise knowledge regarding pathophysiology. So far, first-line treatments still based on monoamine neurotransmitters. Even though there lot progress this field, mechanisms seem get more confusing, also getting controversial. In study, we try review broad advances neurotransmitters field MDD, update effects many advanced neuroscience studies. We propose hypothesis paid special attention their new pathways for such as inflammation, oxidative stress, neurotrophins, neurogenesis, especially glial cells, which have recently been found play important role neurodegenerative disorders, including MDD. addition, will extend basic emotions; suggested our previous reports, three different roles emotions: dopamine—joy, norepinephrine—fear (anger), serotonins—disgust (sadness). Above all, paper tries give full picture relationship between MDD DA, NE, 5-HT, well contributions Three Primary Color Model Basic Emotions (joy, fear, disgust). This done by explaining contribution from sides digestive tract, astrocytes, microglial, others, very briefly addressing potential therapeutic patients reasons limited clinical efficacy, side effects, delayed onset action. hope might offer pharmacological management

Language: Английский

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Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 31, 2021

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder. The mechanisms underlying ASD are unclear. Astrocyte alterations noted in patients and animal models. However, whether astrocyte dysfunction causal or consequential to ASD-like phenotypes mice unresolved. Type 2 inositol 1,4,5-trisphosphate 6 receptors (IP3R2)-mediated Ca2+ release from intracellular stores results the activation of astrocytes. Mutations IP3R2 gene associated with ASD. Here, we show that both IP3R2-null mutant astrocyte-specific conditional knockout display behaviors, such as atypical social interaction repetitive behavior. Furthermore, astrocyte-derived ATP modulates behavior through P2X2 prefrontal cortex possibly GABAergic synaptic transmission. These findings identify potential molecular player pathophysiology

Language: Английский

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Effects of ‘Healthy’ Fecal Microbiota Transplantation against the Deterioration of Depression in Fawn-Hooded Rats

mSystems, Journal Year: 2022, Volume and Issue: 7(3)

Published: April 28, 2022

Depression is a recurrent, heterogeneous mood disorder occurring in more than 260 million people worldwide. Gut microbiome dysbiosis associated with the development of depressive-like behaviors by modulating neuro-biochemical metabolism through microbiome-gut-brain (MGB) axis. Fecal microbiota transplantation (FMT) has been proposed as potential therapeutic solution for depression, but efficiency and mechanism are unknown. Here, we performed an FMT from Sprague-Dawley (SD) rats ('healthy' controls) to Fawn-hooded (FH) (depression model). Pre-FMT, FH exhibited significantly elevated distinct neurotransmitter cytokine levels compared SD rats. Post-FMT, recipients receiving fecal (FH-FH rats) showed aggravated behaviors, while ones (FH-SD had alleviated depressive symptoms, significant increase hippocampal neurotransmitters, decrease some cytokines FH-FH SD-FMT resulted FH-SD rats' gut resembling donors, shift serum metabolome not metabolome. Co-occurrence analysis suggests that prevented recipients' depression via microbial species such Dialister sp., which led metabolic modulation hippocampus enteric nervous system, intestinal barrier, blood-brain barrier. Our results provided new data pointing multiple mechanisms interaction impact on therapy. IMPORTANCE chronic, recurrent mental disease, could make patients commit suicide severe cases. Considering cause symptoms animals MGB axis, modification expected be therapy daily administration probiotics invalid or transient. In this study, demonstrated transferred healthy rat model regulate recipient's neurobiology behavior systematic alternation followed metabolism. These underline significance understanding disorders suggest 'healthy' function solve host's cerebral inflammation may serve novel strategy depression.

Language: Английский

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