ACS Chemical Neuroscience最新文献

{"title":"Dual-Function Fluorescent Probes for Neuronal Trans-Differentiation: A Promising Therapeutic Strategy in Neuroregenerative Research.","authors":"Pratikshya Paudel, Prabir Kumar Gharai","doi":"10.1021/acschemneuro.5c00367","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00367","url":null,"abstract":"<p><p>Neurodegenerative diseases cause progressive neuronal loss, with current treatments offering only limited symptomatic relief. To overcome this, various strategies are being explored. One promising approach involves converting human mesenchymal stem cells (hMSCs) into functional neurons using a small molecule, alongside the use of fluorescent probes for real-time imaging. Therefore, developing a promising single compound that combines both differentiation-inducing and imaging capabilities without relying on growth factors could significantly advance neuroregenerative therapies and diagnostic strategies in neuroscience research.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482491","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":"Fluorometric Nanoscale Analysis of Bilirubin and Biliverdin in Human Cerebrospinal Fluid.","authors":"Paola Sist, Federica Tramer, Arianna Sartori, Paolo Manganotti, Sabina Passamonti","doi":"10.1021/acschemneuro.5c00265","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00265","url":null,"abstract":"<p><p>Cerebrospinal fluid (CSF) is a valuable source for the quantification of soluble, brain-specific biomarkers supporting the diagnosis of some neurological disorders, infectious diseases, and suspected subarachnoid hemorrhage. Given the increasing need to expand the basic knowledge of brain pathophysiology for disease biomarker discovery, we set the goal to quantify bilirubin and biliverdin in human CSF. Their concentrations are expected to reflect the level of brain heme catabolism, a key pathway involved in the biological response to oxidative stress. Here, we present the results of the CSF analysis by a specific and sensitive fluorometric method using the recombinant fusion protein HELP-UnaG (HUG). The concentrations of bilirubin and biliverdin in 50 human CSF samples were in the ranges of 14-340 and 0-66 nM, respectively. This assay can be easily implemented in small-scale laboratories and neurological units for the routine analysis of clinical CSF samples.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482492","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":"Synthesis, Labeling, and Biological Evaluation of P2Y₁₂ Receptor Radioligands for Positron Emission Tomography Imaging of Neuroinflammation.","authors":"Eugénie Pincemail, Marie-Anne Peyronneau, Caroline Denis, Hayet Bensalah, Margot Corbel, Sébastien Goutal, Maud Goislard, Haneen Al Hroub, Marie Théry, Sébastien Beuché, Hashem Ali M Al Musawi, Fabien Chauveau, Nadja Van Camp, Alexis-Pierre Bemelmans, Christa E Müller, Bertrand Kuhnast, Alexandra Winkeler, Mylène Richard","doi":"10.1021/acschemneuro.5c00187","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00187","url":null,"abstract":"<p><p>The P2Y₁₂ receptor (P2Y₁₂R) is a G-protein-coupled receptor whose expression level is directly correlated to microglial activation. Herein, we report on the design of a series of new P2Y₁₂R ligands and the radiolabeling and characterization of two positron emission tomography (PET) tracers, [¹¹C]<b>37</b> and [¹⁸F]<b>41</b>. These compounds were evaluated by autoradiography studies on rat brain slices exhibiting overexpression of human P2Y₁₂Rs (AAV-<i>h</i>P2Y₁₂R). Metabolism and biodistribution of [¹⁸F]<b>41</b> were evaluated ex vivo in healthy rats and indicated good metabolic stability with 41% of unchanged radioligand 1 h post injection and a limited crossing of the blood-brain barrier with a brain uptake of 0.02%ID/g 1 h post injection. In vivo PET imaging performed in the AAV-<i>h</i>P2Y₁₂R rat model confirmed this low brain uptake, and no significant difference was found in the transfected (SUV_mean 0.14 ± 0.01) versus contralateral (SUV_mean 0.13 ± 0.01) striatum of the AAV-<i>h</i>P2Y₁₂R model. Similar results were observed in healthy rats and in nonhuman primates. Additional studies in the presence of tariquidar led to a 3-4-fold increase in the [¹⁸F]<b>41</b> brain concentration, suggesting that [¹⁸F]<b>41</b> is a P-glycoprotein substrate. Future work will focus on improving radioligand design to enhance blood-brain barrier permeation and to reduce efflux transport.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473285","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":"Microgravity-Assisted Exploration of the Conformational Space of Amyloid β Affected by Tottori-Type Familial Mutation D7N.","authors":"Maho Yagi-Utsumi, Saeko Yanaka, Raymond N Burton-Smith, Chihong Song, Christian Ganser, Chiaki Yamazaki, Haruo Kasahara, Toru Shimazu, Takayuki Uchihashi, Kazuyoshi Murata, Koichi Kato","doi":"10.1021/acschemneuro.5c00217","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00217","url":null,"abstract":"<p><p>The amyloid β (Aβ) Tottori variant (D7N) exhibits unique aggregation behaviors and altered fibril formation, posing challenges for structural characterization. To overcome this, the microgravity environment on the International Space Station was employed to study Tottori-type Aβ40 fibril formation and structure. Under Earth gravity, Tottori-type Aβ40 primarily formed nonfibrillar aggregates, hindering detailed structural analysis. In contrast, microgravity significantly enhanced fibril formation and minimized amorphous aggregates. Cryo-electron microscopy revealed two structurally distinct fibril types, each comprising different protomer conformations. In both types, the N-terminal segment was disordered and nor resolved in the density maps. The D7N mutation disrupts the protection of the core by the N-terminal segment often observed in wild-type Aβ40 fibrils, enhancing the hydrophobicity-mediated aggregation propensity. However, microgravity suppressed kinetic traps and facilitated high-quality fibril formation suitable for structural studies that can explore the free energy landscape of Aβ fibril formation. These findings demonstrate the utility of microgravity for studying familial Aβ variants and potentially accelerate our understanding of Aβ aggregation mechanisms in Alzheimer's disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482493","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":"Machine Learning Model for Predicting Sertraline-like Activities and Its Impact on Cancer Chemosensitization.","authors":"Jin-Yu Xia, Ze-Yu Sun, Ying Xue, Ying-Qian Zhang, Zhi-Wei Feng, Yu-Long Li","doi":"10.1021/acschemneuro.5c00165","DOIUrl":"10.1021/acschemneuro.5c00165","url":null,"abstract":"<p><p>Selective serotonin reuptake inhibitors (SSRIs) like sertraline are crucial in treating depression and anxiety disorders, and studies indicate their potential as chemosensitizers in cancer therapy. This research develops a machine-learning predictive model to identify novel compounds with sertraline-like antidepressant activity. We constructed and validated a customized machine-learning model to predict SSRI activity in new compounds. By applying feature engineering to the chemical structures and bioactivity data of sertraline and its analogs, we trained multiple machine-learning algorithms. Through extensive comparative analysis, we found that the support vector machine (SVM) model demonstrated exceptional performance, achieving an accuracy rate of up to 93%. By further optimizing and integrating the SVM model, we successfully enhanced its accuracy, reaching an impressive 95% capability in predicting more active SSRI compounds. This study successfully developed a targeted, rapid, and efficient machine learning model capable of accurately predicting SSRI activity. The model serves as a valuable tool for rapidly screening novel SSRI drug candidates with superior activity, bringing immense value to the field of drug development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473284","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":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 12","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/cnv016i012_1948816","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422840","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":"Discovery of Carbazole and Theophylline-Based Amyloid Inhibitor for the Promotion of Neuroprotection.","authors":"Prabir Kumar Gharai, Juhee Khan, Rathnam Mallesh, Shubham Garg, Sanju Gupta, Parasuraman Jaisankar, Surajit Ghosh","doi":"10.1021/acschemneuro.5c00067","DOIUrl":"10.1021/acschemneuro.5c00067","url":null,"abstract":"<p><p>The amyloid-beta 42 (Aβ₄₂) peptide assembles into neurotoxic soluble oligomers and extracellular fibrillary aggregates during the progression of Alzheimer's disease (AD), which ultimately leads to amyloid plaque in the brain, causing major disruption of the neural circuit and leading to the severe loss of memory. Thus, perturbation or inhibition of this process through the development of advanced inhibitors is crucial for the treatment of AD. Here, we adopted an advanced strategy that showcases the design of a carbazole-based chemical inhibitor targeting the Aβ peptide. The new inhibitors are designed in such a way that they can bind selectively with the Aβ₄₂ peptide and inhibit the assembly process and disease progression. Initial assessments using the thioflavin-T assay and molecular docking experiments help screen the carbazole and theophylline-based CT-01 as effective lead molecules, which bind at the N-terminal hydrophobic region of the Aβ₄₂ peptide and inhibit the formation of soluble oligomers and extracellular fibrillary aggregates. Further, FT-IR spectroscopy, CD, TEM, dot blot, and ITC experiments suggest the inhibition potency of CT-01. Finally, the neuroprotection and apoptosis assay confirm that CT-01 reduces amyloid-mediated toxicity in neurons. The serum-stable CT-01 can also protect the NGF-deprived neurons and has the ability to cross the blood-brain barrier.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2224-2236"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186062","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":"Electric Patch-Clamp Probing and Computational Studies of Lipid Bilayer Structural Fluctuations Induced by Methylamphetamine on a Neuronal Cell Membrane.","authors":"Hashini R Eheliyagoda, H Peter Lu","doi":"10.1021/acschemneuro.5c00088","DOIUrl":"10.1021/acschemneuro.5c00088","url":null,"abstract":"<p><p>Investigating how the central nervous system stimulant methylamphetamine (METH) disrupts neuronal cell membranes is crucial, as lack of knowledge of the molecular-level disruptions-such as complex solvation dynamics and alterations in the lipid bilayer structure and texture-caused by the interaction of these lipophilic drugs with neuronal membranes. Even though detection of these drug-induced disruptions of the neuronal membrane is technically challenging, we were able to measure the electrical current fluctuation changes of the disrupted HT22 neuronal cell membrane upon interacting with METH using whole-cell patch-clamp combined differential interference contrast microscopy. Furthermore, we carried out molecular dynamics (MD) simulation studies to investigate the permeation of METH into the lipid bilayer and to study the interaction between lipids and METH. We observed that the fluidity and permeability fluctuations of the HT22 cell membrane have increased in the presence of METH molecules in a concentration-dependent manner resulting in higher electric leaking states for higher METH concentrations used, which have more electric conductance compared to the nonleaking states. Analyzing the autocorrelation function fittings for the leaking vs nonleaking electric current activities, we were able to characterize the conformational dynamics and randomness of the cell membrane permeability fluctuations to study the recovery rate of the bilayer from the temporarily perturbed state. MD simulations with quantitative free energy analysis revealed that the METH molecules easily permeate into the lipid bilayer showing METH-cluster formations and accumulations inside the lipid bilayer close to the lipid headgroup's level region and showing subsequent interactions with lipid head groups and dragging bulk water molecules into the bilayer. Also, we observed that the formed METH clusters for higher METH concentrations do not penetrate the bilayer as a cluster. Instead, interestingly single METH molecule penetration per time into the bilayer from the METH cluster was observed from our MD results, illustrating the leaking vs nonleaking behaviors detected for patch-clamp experiments. Applying our combined new approach, we obtained results with real-time permeability changes and computational observations of the cell membrane due to METH-induced disruptions, which provides comprehensive knowledge important to studying the drug disturbance of crucial cellular functions such as solvation dynamics fluctuations and the molecular behavior of METH in the water lipid interface.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2260-2276"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245191","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":"New K_V7.2/3 Channel Activators Exhibit Superior Toxicity and Metabolic Profiles to Flupirtine and Demonstrate Promising <i>In Vivo</i> Analgesic Effects.","authors":"Frieda-Marie Bartz, Kinga Sałat, Katarzyna Urbańska, Jana Lemke, Pascal Rosendahl, Louis Schmidt, Lukas Schulig, Ulrike Garscha, Andreas Link, Patrick J Bednarski","doi":"10.1021/acschemneuro.5c00278","DOIUrl":"10.1021/acschemneuro.5c00278","url":null,"abstract":"<p><p>The first-in-class K_V7.2/3 channel activator flupirtine, was considered a potent analgesic in various pain conditions. However, it was withdrawn from the market in 2018 due to severe hepatotoxicity associated with forming reactive metabolites. In this work, we present new K_V7.2/3 channel modulators that have been evaluated in several preclinical mouse pain models, including acute thermally and chemically induced pain, diabetes-induced neuropathic pain, and chemotherapy-induced peripheral neuropathy. In addition, the new K_V7.2/3 channel activators were compared with the reference substances flupirtine, retigabine, and azetukalner, focusing on the inhibition of the hERG channel, nephrotoxicity, metabolic stability, and the formation of reactive metabolites. A flupirtine analog with a pyrimidine scaffold (<b>8</b>) showed clear advantages over the reference compounds tested, with a favorable toxicity profile, a 2 h <i>in vitro</i> half-life when incubated with human liver microsomes, and a 9-fold reduction in the formation of reactive metabolites compared to flupirtine. This compound also demonstrated strong <i>in vivo</i> efficacy in pain models, making it a promising candidate for further development of K_V7.2/3 channel activators.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2322-2333"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256628","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":"","authors":"Hung Nguyen Do,&nbsp;Jessica Z. Kubicek-Sutherland and Sandrasegaram Gnanakaran*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 12","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.4c00760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144422846","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}