ACS Chemical Neuroscience最新文献

{"title":"An Amyloidogenic Fragment of the Spike Protein from SARS-CoV-2 Virus Stimulates the Aggregation and Toxicity of Parkinson’s Disease Protein Alpha-Synuclein","authors":"João Flavio Gemignani,&nbsp;Paulo Augusto Netz,&nbsp;Daniel Izecksohn,&nbsp;David Dabkiewicz,&nbsp;Ming-Hao Li,&nbsp;Adalgisa Felippe Wiecikowski,&nbsp;David Eliezer,&nbsp;Yraima Cordeiro and Cristian Follmer*,&nbsp;","doi":"10.1021/acschemneuro.5c00478","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00478","url":null,"abstract":"<p >Emerging evidence suggests that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have long-term deleterious effects on the central nervous system and even contribute to post-COVID neurological syndromes. Interestingly, inflammation-induced proteolytic processing of the Spike protein of SARS-CoV-2 leads to the generation of peptides capable of aggregating into amyloid fibrils <i>in vitro</i>. Herein, we investigate the <i>in vitro</i> effect of a fibrillogenic fragment of the Spike protein [Spike 194–203 (S194)] on the aggregation and toxicity of the Parkinson’s disease (PD) protein α-synuclein (αSyn). Our results indicate that S194 fibrils stimulate in a concentration-dependent manner the fibrillation of αSyn monomer, resulting in aggregates with increased capacity of inducing lipid vesicle leakage and toxicity to neuroblastoma cells, in comparison with either αSyn or S194 alone. Bidimensional NMR (¹H–¹⁵N-HSQC) suggests that S194 fibrils cause a higher perturbation in both the N-terminal region (sequence: 19–68) and the hydrophobic central domain of the αSyn monomer (sequence: 71–95), which is corroborated by protein–peptide docking and molecular dynamics simulations. In contrast with fibrils from wild-type αSyn, aggregates from the PD variant A30P exhibited a remarkable accelerative effect on S194 fibrillation. Similarly, fibrils from amyloid-β peptides, which are linked to Alzheimer’s disease, exhibited a pro-aggregating effect on the S194 monomer. Taken together, these findings might contribute to a broader understanding of the potential connections between SARS-CoV-2 infection and amyloid-related neurodegenerative disorders, highlighting areas that may warrant further investigation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3385–3397"},"PeriodicalIF":3.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00478","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Nonelectrophilic and Selective TRPA1 Agonist for Alleviation of Inflammatory Pain through Channel Desensitization","authors":"Chaoyue Sun,&nbsp;Nan Yang,&nbsp;Ting Xin,&nbsp;Xiangying Kong,&nbsp;Ningning Wei* and Zhen Qiao*,&nbsp;","doi":"10.1021/acschemneuro.5c00258","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00258","url":null,"abstract":"<p >Transient receptor potential ankyrin 1 (TRPA1) agonists exert long-lasting analgesic effects by inducing neuronal desensitization, a similar strategy has been confirmed in the approval of capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist for the management of neuropathic pain associated with postherpetic neuralgia. However, currently available TRPA1 agonists are limited by insufficient selectivity or undesirable side effects, highlighting the urgent need for the discovery of novel TRPA1 agonists as potential analgesics. In this study, we reported a selective TRPA1 agonist <i>N</i>-(3-methoxypropyl)-4-(<i>p</i>-tolyl)thiazol-2-amine named NMTA based on screening our compound library. Calcium imaging and whole-cell patch clamp recordings demonstrated NMTA as a TRPA1 agonist with an EC₅₀ value of 50.05 ± 5.39 μM for <i>h</i>TRPA1. Repetitive administration of NMTA caused channel desensitization in TRPA1-overexpressing HEK-293T cells, suggesting a potential analgesic effect <i>in vivo</i>. Oral administration of NMTA significantly alleviated pain hypersensitivity in Complete Freund’s Adjuvant (CFA)-induced inflammatory pain in mice, indicating an analgesic effect of NMTA for inflammatory pain. Molecular docking suggested T684 was critical for the activation of NMTA on TRPA1 channel. In summary, we have identified NMTA as a highly selective TRPA1 agonist capable of alleviating inflammatory pain in mice through channel desensitization, thereby verifying a feasible strategy for developing TRPA1-targeted analgesics based on desensitization.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3257–3266"},"PeriodicalIF":3.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of Neuronal Glutamate in Brain Extracellular Space In Vivo Using Microdialysis and Metabolic Labeling with Glutamine","authors":"Neil D. Hershey,&nbsp;Pavlo Popov,&nbsp;Nick Oliver,&nbsp;Colleen E. Dugan and Robert T. Kennedy*,&nbsp;","doi":"10.1021/acschemneuro.5c00518","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00518","url":null,"abstract":"<p >Extracellular glutamate (Glu) concentration measured in the brain using microdialysis sampling is regulated differently from that expected for classical neurotransmitters; e.g., the basal Glu concentration is not affected by blocking action potentials. Additionally, other sources, such as glial cells, contribute to Glu extracellular concentration making it difficult to interpret detected changes. We have found that infusing 2.5 μM ¹³C₅-glutamine (Gln) through a microdialysis probe inserted in the rat cortex results in collection of 144 ± 35 nM (<i>n</i> = 11) ¹³C₅-Glu in dialysate. The recovered ¹³C₅-Glu was reduced by 33% by infusion of 20 mM α-(methylamino)isobutyric acid and 58% by 500 mM riluzole, inhibitors of glutamine transport into neurons. The ¹³C₅-Glu measured was reduced by 62% with tetrodotoxin (TTX), a sodium channel blocker, and 59% with (1<i>S</i>,3<i>R</i>)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a metabotropic glutamate agonist, while endogenous Glu remained unchanged. These results support the hypothesis that the measured ¹³C₅-Glu is derived from neurons via the Gln-Glu shuttle. To further investigate regulation of ¹³C₅-Glu, we applied a stressor (tail pinch), observing a 155% increase in dialysate ¹³C₅-Glu concentration. This effect was blocked by infusion of TTX indicating neuronal release. Local infusion of <span>l</span>-<i>trans</i>-pyrrolidine-2,4-dicarboxylic acid (PDC), a Glu uptake inhibitor, increased both endogenous Glu and ¹³C₅-Glu concentrations, consistent with reverse transport and spread of neuronal release. Taken together, these experiments show that metabolic labeling of Glu via Gln delivered through a microdialysis probe allows differentiation of neuronal and other sources of Glu in the brain. The results support the concept of compartmentalized Glu in the brain.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3398–3409"},"PeriodicalIF":3.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Crafting Precision: Design and Fabrication of Xurography-Driven Microfluidic Platform for Exploring Neuron Culture and Targeted Drug Screening”","authors":"Subhadra Nandi,&nbsp;Arijit Bera,&nbsp;Satyajit Ghosh,&nbsp;Anindyasundar Adak,&nbsp;Rajsekhar Roy and Surajit Ghosh*,&nbsp;","doi":"10.1021/acschemneuro.5c00630","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00630","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3410"},"PeriodicalIF":3.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen Sulfide–Releasing Insulin Polypeptide Mitigates Hyperglycemia-Induced Neurotoxicity and Cognitive Deficits In Vivo","authors":"Rafat Ali,&nbsp;Shantanu Sen,&nbsp;Rohil Hameed,&nbsp;Arshi Waseem,&nbsp;Swapnil Raj Gautam,&nbsp;Akanksha Onkar,&nbsp;Subramaniam Ganesh,&nbsp;Syed Shadab Raza,&nbsp;Aamir Nazir and Sandeep Verma*,&nbsp;","doi":"10.1021/acschemneuro.5c00390","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00390","url":null,"abstract":"<p >Hyperglycemia, a characteristic of diabetes, is increasingly associated with an elevated risk of neurodegenerative disorders, such as Parkinson’s disease. Hyperglycemia serves as a comorbidity and hastens neurodegenerative processes in Parkinson’s disease. We report the development of H₂S-releasing human insulin polypeptide (SHI), which will colocalize metabolic release of H₂S near insulin action, and a thorough investigation of their combined efficacy in mitigating Parkinson’s disease and hyperglycemia-associated symptoms. SHI demonstrated notable neuroprotective effects in SH-SY5Y human neuroblastoma cells subjected to elevated glucose concentrations and the neurotoxin 6-OHDA. In transgenic <i>Caenorhabditis elegans</i> Parkinson’s disease model, SHI reduced the levels of human α-Synuclein, while increasing the levels of dopamine transporter. Moreover, SHI showed behavioral improvements in both <i>Drosophila</i> and <i>C. elegans</i>, highlighting its potential therapeutic applications. This approach addresses both neurodegenerative and metabolic pathways, providing dual benefits for these interrelated conditions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3323–3339"},"PeriodicalIF":3.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Copper Chelators Enhance Spatial Memory and Biochemical Outcomes in Alzheimer’s Disease Model","authors":"Mariana L. M. Camargo,&nbsp;Augusto B. Farias,&nbsp;Giovana B. Bertazzo,&nbsp;Rafael N. Gomes,&nbsp;Kaio S. Gomes,&nbsp;Lucas M. Bosquetti,&nbsp;Silvia H. Takada,&nbsp;Felipe C. Braga,&nbsp;Caroline C. Augusto,&nbsp;Bruno L. Batista,&nbsp;Kleber T. de Oliveira and Giselle Cerchiaro*,&nbsp;","doi":"10.1021/acschemneuro.5c00291","DOIUrl":"10.1021/acschemneuro.5c00291","url":null,"abstract":"<p >This study explores the potential of novel molecules that can act as copper chelators to treat Alzheimer’s disease. Eight imines <b>L03–10</b> and one quinoline-based compound <b>L11</b> were synthesized, characterized, and evaluated as compounds that can act to reverse neurodegeneration in vivo. Their ability to extract copper from the Cu-β-amyloid complex, a key factor in Alzheimer’s pathology, was assessed, achieving a remarkable in vitro activity for <b>L09</b>, <b>L10</b>, and <b>L11</b>. They effectively extracted it from the Cu-β-amyloid complex, which was confirmed using electron paramagnetic resonance (EPR) spectroscopy. In silico studies predicted that compounds <b>L09</b>, <b>L10</b>, and <b>L11</b> demonstrated favorable absorption, distribution, metabolism, and excretion (ADME) properties, suggesting suitability for oral administration and blood-brain barrier permeability. Cellular studies showed that compounds <b>L09</b> and <b>L10</b> (at concentrations up to 500 μM) exhibited low cytotoxicity. They reduced lipid peroxidation and DNA damage induced by beta-amyloid oligomers at lower concentrations. Compound <b>L11</b> showed more significant cytotoxicity but reduced beta-amyloid-induced DNA damage. In vivo studies (STZ-induced Alzheimer’s rat model) proved that compound <b>L10</b> significantly reduced neuroinflammation, oxidative stress, and restored copper homeostasis in the hippocampus. This was accompanied by improved spatial memory performance in the Barnes maze test. Compounds <b>L09</b> and <b>L11</b> showed less impact on these parameters. The study presents compelling evidence that specifically designed copper chelators could offer a new therapeutic strategy for Alzheimer’s disease. Compound <b>L10</b> is an up-and-coming candidate and warrants further investigation. The detailed in silico, in vitro, and in vivo analyses provide a solid motivation for future research and drug development efforts.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3267–3281"},"PeriodicalIF":3.9,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of [18F]F-CNBI and [18F]F-CNPI PET Probes in GSK-3β Transgenic Mice","authors":"Manasa Kethamreddy,&nbsp;Surendra Reddy Gundam,&nbsp;Andy Gonzalez Rivera,&nbsp;Aditya Bansal,&nbsp;Do Young Lim,&nbsp;Sharmila Giri,&nbsp;Nicholas B. Larson,&nbsp;Bharath Wootla,&nbsp;Val J. Lowe,&nbsp;Darren J. Baker and Mukesh K. Pandey*,&nbsp;","doi":"10.1021/acschemneuro.5c00442","DOIUrl":"10.1021/acschemneuro.5c00442","url":null,"abstract":"<p >The present study explores the noninvasive positron emission tomography (PET) imaging for the detection of GSK-3β overexpression using [¹⁸F]F-CNPI and [¹⁸F]F-CNBI in a GSK-3β overexpressing transgenic mouse model. Herein, we validated GSK-3β overexpression in different brain regions by genotyping and Western blot. PET scans and ex vivo biodistribution were performed in normal mice and early stage and late-stage GSK-3β transgenic mice with and without the P-gp inhibitor, Tariquidar. Both probes are found in the substrate of the P-gp transporter. [¹⁸F]F-CNPI showed significantly higher brain uptake in normal and GSK-3β overexpressing mice with the P-gp inhibitor compared to those without the P-gp inhibitor. The uptake of [¹⁸F]F-CNBI was lower in all the groups compared to that of [¹⁸F]F-CNPI. The late-stage GSK-3β transgenic mice having higher GSK-3β expression showed higher uptake of [¹⁸F]F-CNPI in the brain as compared to normal and early stage GSK-3β transgenic mice brains. To the best of our knowledge, this is the first report evaluating any GSK-3 PET probe in a GSK-3β overexpressing transgenic mouse model. The developed GSK-3β overexpressing transgenic mouse model can be efficiently employed to evaluate an array of GSK-3 PET probes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3340–3353"},"PeriodicalIF":3.9,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Evaluation of Tropane Analogues at the Serotonin Transporter","authors":"Arabo A. Avanes,&nbsp;Hunter T. Warren,&nbsp;Abinaya Senthil and David E. Olson*,&nbsp;","doi":"10.1021/acschemneuro.5c00443","DOIUrl":"10.1021/acschemneuro.5c00443","url":null,"abstract":"<p >Tropane alkaloids and their derivatives represent a diverse class of small molecules with a broad range of therapeutic applications. Many tropanes regulate synaptic levels of neuromodulators by interacting with monoamine transporters such as dopamine (DAT) and serotonin (SERT) transporters. While DAT inhibition plays an important role in the addictive potential of tropanes such as cocaine, recent evidence suggests that SERT modulation may oppose the effects of DAT inhibition. Moreover, SERT modulators such as 3,4-methylenedioxymethamphetamine (MDMA), ibogaine, and selective-serotonin reuptake inhibitors (SSRIs) have demonstrated potential as treatments for a broad range of conditions, including depression, addiction, and post-traumatic stress disorder (PTSD). Here, we profiled a variety of structurally distinct subclasses of tropanes in SERT inhibition, efflux, and pharmacochaperone assays. We identified several compounds capable of potently modulating SERT in ways similar to those of fluoxetine, MDMA, or noribogaine. In particular, <b>UCD0168</b> and <b>UCD0820</b> emerged as potent SERT inhibitors that act as full and partial serotonin releasing agents (SRAs) in SERT-transfected HEK293T cells, respectively. Our work demonstrates that it is possible to use the tropane scaffold as a starting point for identifying both MDMA-like and noribogaine-like SERT modulators, and we provide several new tropane-containing hit structures for creating optimized therapeutics relying on SERT modulation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3354–3363"},"PeriodicalIF":3.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fiber Photometry Analysis of Spontaneous Dopamine Signals: The Z-Scored Data Are Not the Data","authors":"Conner W. Wallace,&nbsp;Emily K. DiMarco,&nbsp;Clare Y. Slinkard,&nbsp;Rachael Shaughnessy,&nbsp;Katherine M. Holleran,&nbsp;Samuel W. Centanni,&nbsp;Christopher C. Lapish and Sara R. Jones*,&nbsp;","doi":"10.1021/acschemneuro.5c00078","DOIUrl":"10.1021/acschemneuro.5c00078","url":null,"abstract":"<p >Fluorescent sensors have revolutionized the measurement of molecules in the brain, and the dLight dopamine sensor has been used extensively to examine reward- and cue-evoked dopamine release, but only recently has the field turned its attention to spontaneous release events. Analysis of spontaneous events typically requires evaluation of hundreds of events over minutes to hours, and the most common method of analysis, <i>z</i>-scoring, was not designed for this purpose. Here, we compare the accuracy and reliability of three different analysis methods to identify pharmacologically induced changes in dopamine release and uptake in the nucleus accumbens core of freely moving C57BL/6J mice. The D1-like receptor antagonist SCH23390 was used to prevent dLight sensors from interacting with dopamine in the extracellular space, while cocaine was used to inhibit uptake and raclopride to increase the release of dopamine. We examined peak-to-peak frequency, peak amplitude, and width, the time spent above an established cutoff. The three methods were (1) the “<i>Z</i>-score method”, which automatically smooths baseline drift and normalizes recordings using signal-to-noise ratios; (2) a “manual method”, in which local baselines were adjusted manually and individual cutoffs were determined for each subject; and (3) the “prominence method” that combines <i>z</i>-scoring with prominence assessment to tag individual peaks and then returns to the preprocessed data for kinetic analysis. First, SCH23390 reduced the amplitude of release, but this effect was diminished using the Z-score method, and there was a variable effect on frequency between methods. Cocaine increased signal width as expected using the manual and prominence methods but not the Z-score method. Finally, raclopride-induced increases in amplitude were correctly identified by all three methods, but this effect was again diminished by using the Z-score method. Thus, analysis of spontaneous dopamine signals requires assessment of the %Δ<i>F</i>/<i>F</i> values, and the use of <i>z</i>-scoring is not appropriate.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3239–3256"},"PeriodicalIF":3.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Cyclooxygenase-2 Inhibitors in Preclinical Rodent Models of Depression and Post-traumatic Stress Disorder: A Systematic Review of Behavioral, Neuroinflammatory, and Molecular Mechanisms","authors":"Alexey Sarapultsev*,&nbsp;Maria Komelkova,&nbsp;Irina Utepova,&nbsp;Evgenii Gusev,&nbsp;Desheng Hu,&nbsp;Alexander Trofimov,&nbsp;Tursonjan Tokay,&nbsp;Elena Kondaurova and Vladimir Naumenko,&nbsp;","doi":"10.1021/acschemneuro.5c00568","DOIUrl":"10.1021/acschemneuro.5c00568","url":null,"abstract":"<p >Depression and post-traumatic stress disorder (PTSD) are treatment-resistant neuropsychiatric conditions closely linked to chronic neuroinflammation. Given the limitations of current pharmacotherapies, selective cyclooxygenase-2 (COX-2) inhibitors have emerged as promising candidates for modulating neuroimmune and oxidative pathways. This systematic review evaluated the efficacy of selective COX-2 inhibitors in improving behavioral and neuroinflammatory outcomes in rodent models of chronic stress or systemic inflammation relevant to depression and PTSD. A comprehensive search was conducted across PubMed, Scopus, Web of Science, and other databases for in vivo rodent studies published between 2010 and 2025. Inclusion criteria required validated chronic stress or inflammation paradigms (≥7 days), selective COX-2 inhibitors, and reporting of quantitative behavioral and neuroinflammatory end points. Thirty-four studies met eligibility criteria and were synthesized both qualitatively and via targeted random-effects meta-analysis for depression-like behaviors. COX-2 inhibitors such as celecoxib, meloxicam, and etoricoxib reduced forced swim test immobility by approximately 40% and increased sucrose preference by 25–30%, effects comparable to or exceeding SSRIs. Reductions in IL-6, TNF-α, and COX-2 expression ranged from 30% to 60%, along with suppression of the NF-κB pathway and markers of glial activation (Iba-1, GFAP). Concurrent activation of antioxidant pathways via Nrf2/HO-1 led to elevated levels of SOD, GSH, and BDNF, which correlated with behavioral improvements. A pooled meta-analysis (<i>n</i> = 15 comparisons) revealed a large standardized effect size (Hedges’ <i>g</i> = 3.19; 95% CI: 2.14–4.25; <i>I</i>² = 92.2%) in favor of COX-2 inhibition. While findings consistently support these agents’ antidepressant- and anxiolytic-like efficacy in chronic stress models, their translational potential is limited by male-restricted samples (91% of studies), underreporting of effect sizes, and a scarcity of long-term durability assessments. These results support continued investigation of COX-2 inhibitors as adjunctive treatments in stress-related psychiatric disorders, with an emphasis on sex-stratified analyses and standardized behavioral and molecular reporting.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 16","pages":"3096–3114"},"PeriodicalIF":3.9,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}