ACS Chemical Neuroscience最新文献

{"title":"Damage of the Phospholipid Bilayer by Aβ42 at Physiologically Relevant Peptide Concentrations.","authors":"Ruan van Deventer, Yuri L Lyubchenko","doi":"10.1021/acschemneuro.4c00647","DOIUrl":"10.1021/acschemneuro.4c00647","url":null,"abstract":"<p><p>Amyloid β (Aβ) aggregates are implicated in the pathology of several neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, and damage to membranes is considered one of the pathology-related effects of Aβ. Experiments in vitro indicate that Aβ can damage these membranes; however, such experiments were performed at Aβ concentrations in the micromolar range, several orders above the physiologically relevant conditions. Our studies with Aβ42 in the low nanomolar concentrations did not reveal any damage to the supported lipid bilayer, questioning this membrane damage mechanism of Aβ. However, the phospholipid composition can be a factor contributing to the interaction of Aβ with the membrane. Therefore, in this study, we investigated the interaction of 50 nM Aβ42 with supported lipid bilayers composed of equimolar ratios of POPS and POPC at phospholipid concentrations of 0.1 and 0.25 mg/mL. Using atomic force microscopy (AFM), we observed that Aβ42 induced damage to bilayers at 0.1 mg/mL, characterized by forming defects that grew in size and number over time. The defects penetrate only the upper leaflet of the bilayer, but no such defects were observed at 0.25 mg/mL phospholipid concentrations. We additionally determined Young's modulus of these bilayers as a measure of stiffness, and these values were 6.9 ± 3.6 MPa and 16.6 ± 5.3 MPa for the 0.1 mg/mL and the 0.25 mg/mL bilayers, respectively. These findings suggest that Aβ42's ability to induce bilayer damage depends on membrane stiffness, with softer bilayers (0.1 mg/mL) being more susceptible to Aβ42-induced damage. The results are discussed and compared with models in which Aβ42 oligomers create localized membrane damage. The implication of the results to the mechanisms of the Aβ42 oligomer pathology is discussed.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4559-4567"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685392","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 Perspective on Sevoflurane-Induced Cognitive Dysfunction: Implications of Neuronal SIRPα and Microglial Synaptic Remodeling.","authors":"Wei Du, Xiaomin Zhang, Songze Li, Xin Xie","doi":"10.1021/acschemneuro.4c00485","DOIUrl":"10.1021/acschemneuro.4c00485","url":null,"abstract":"<p><p>This study aims to investigate the role of neuronal SIRPα and microglial synaptic remodeling in sevoflurane-induced cognitive dysfunction in newborn mice. Newborn mice were exposed to sevoflurane, followed by behavioral assessments and single-cell transcriptome sequencing of cortical cells. Lentivirus-mediated overexpression of neuronal SIRPα and assessment of the microglial morphology and synaptic function were conducted. Sevoflurane exposure resulted in social cognitive impairments without affecting motor coordination. Transcriptomic analysis revealed no significant changes in cortical microglial cells or neurons. However, sevoflurane inhibited nonsynaptic synapse modification by microglia. Overexpression of neuronal SIRPα enhanced microglial function, promoted neuron development, and ameliorated cognitive impairments. SCENIC analysis identified a correlation between IRF8 and SIRPα expression. This study sheds light on the involvement of neuronal SIRPα and microglial synaptic remodeling in sevoflurane-induced cognitive dysfunction. Understanding these mechanisms offers new avenues for exploring cognitive impairment pathways and potential therapeutic targets.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4500-4516"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790500","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":"Evaluation of the Neuroprotective Effect of Total Glycosides of <i>Cistanche deserticola</i> and Investigation of Novel Brain-Targeting Natural MAO-B Inhibitors.","authors":"Xinyuan Zhai, Wenyu Xie, Muhammad Danish Yaqoob, Feng Zhao, Hong Zhe Zhu, Shang Shen Yang, Kai Wang, Xumei Wang, Hai Chao Wang, Xiaoming Wang","doi":"10.1021/acschemneuro.4c00608","DOIUrl":"10.1021/acschemneuro.4c00608","url":null,"abstract":"<p><p>In this study, we investigated the role of total glycosides of <i>Cistanche deserticola</i> (TC) in MPTP-induced neuronal injury. Further, we screened potential inhibitory components of monoamine oxidase B (MAO-B). The study results indicate that TC may improve movement disorders and apoptosis of dopamine (DA) neurons by inhibiting MAO-B activity while reducing the number of glial cells, adjusting the metabolism level of monoamine neurotransmitters, and lowering inflammation and oxidative stress levels. Subsequently, a rapid screening method for drug-containing brain tissue was further constructed, and five candidate components that can cross the blood-brain barrier and bind to MAO-B were screened and submitted for biological activity evaluation and inhibition mechanism research. In summary, we discovered 2'-acetylacteoside as a promising and reversible mixed natural MAO-B inhibitor in TC and developed a rapid screening method for screening central nervous system drugs with blood-brain barrier permeability characteristics, providing potential candidates and an effective screening strategy for neurodegenerative diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4544-4558"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694873","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":"Polymeric Nanodiscs Comprising 5-Fluorouracil for Inhibition of Protein Aggregation and Their Anti-Alzheimer's Activity in the <i>Drosophila</i> Model.","authors":"Pranita Rananaware, Seekha Naik, Lokanath Mishra, Rangappa S Keri, Monalisa Mishra, Varsha P Brahmkhatri","doi":"10.1021/acschemneuro.4c00458","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00458","url":null,"abstract":"<p><p>Nanoconjugates are promising for therapeutic drug delivery and targeted applications due to the numerous opportunities to functionalize their surface. The present study reports the synthesis of 5-fluorouracil (5-FU)-entrapped polyvinylpyrrolidone (PVP) nanoconjugates, precisely 5-FU-PVP and 5-FU-PVP-Au, and the evaluation of protein aggregation inhibition efficiency. The 5-FU-loaded polymer nanoconjugates were functionalized with gold nanoparticles and analyzed using characterization techniques like dynamic light scattering, UV-visible spectroscopy, Fourier-transform infrared spectroscopy, and zeta potential analysis. These conjugates exhibit consistent morphology with a spherical, flat, disc-like structure. The 5-FU-PVP and 5-FU-PVP-Au nanoconjugates exhibited a high drug loading, up to 81% and 90%, respectively. The nanoconjugates exhibited prolonged drug delivery of 5-FU from 5-FU-PVP and 5-FU-PVP-Au, wherein 5-FU-PVP-Au depicted a higher drug release. They were investigated for inhibiting the protein hen egg white lysozyme (HEWL) aggregation by ThT fibril size measurement, binding assay, and electron microscopy, and the results showed that conjugates repressed the fibrillogenesis in HEWL. The prominent activity of amyloid aggregation inhibition for HEWL using 5-FU-PVP and 5-FU-PVP-Au was found to be 29 μg.mL^-1 and 27 μg.mL^-1, respectively. The dissociation of amyloid aggregates was achieved against 5-FU-PVP and 5-FU-PVP-Au at 27 μg.mL^-1 and 25 μg.mL^-1, respectively. Furthermore, the nanoconjugates were investigated for anti-Alzheimer's activity in the <i>Drosophila</i> model. A <i>Drosophila</i> model of Alzheimer's disease (AD) was developed that expressed Aβ42 peptides in the neuronal secretory system to comprehend the pathogenic effects of Aβ42 <i>in vivo.</i> All the results demonstrate that polymer nanoconjugates exhibit more effective inhibition of protein aggregation than bare drugs.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851642","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":"¹H NMR-Based Metabolomic Signatures in Rodent Models of Sporadic Alzheimer's Disease and Metabolic Disorders.","authors":"Ananya Shukla, Khushbhu Meena, Ashish Gupta, Rajat Sandhir","doi":"10.1021/acschemneuro.4c00510","DOIUrl":"10.1021/acschemneuro.4c00510","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a chronic neurological disorder that impacts the elderly population all over the globe. Evidence suggests association between AD and metabolic disorders such as diabetes mellitus (DM) and obesity (OB). The present study is an attempt to evaluate metabolic alterations in the serum and brain through NMR spectroscopy with the aim to identify shared metabolic signatures. AD was induced in rats by stereotactic intracerebroventricular injection of oligomerized Aβ-42 peptide into the brain. DM and OB were induced by intraperitoneal injection of streptozotocin and feeding rats on a high-fat diet, respectively. The metabolic alterations obtained through ¹H NMR spectroscopy were further subjected to multivariate analysis by principal component analysis and partial least-squares discrimination for identification of metabolic signatures. In the serum, the levels of lactate and betaine were increased in AD, DM, and OB rats. On the other hand, the metabolite profile of brain indicated increase in the levels of lactate, <i>N</i>-acetylaspartate, and creatinine in AD, DM, and OB rats. Additionally, the concentration of neurochemicals such as glutamate, GABA, <i>N</i>-acetylglutamate, and myo-inositol were also elevated. The alterations in neurotransmitters and cerebral energy metabolism were accompanied by deficits in cognition assessed by Morris water maze in AD, DM, and OB rats. The perturbed metabolic profiles were accompanied by the presence of pathogenic amyloid deposits visualized by Congo red stain in the brains of AD, DM, and OB rats. Overall, the study identifies common metabolic signatures in AD, DM, and OB that may be involved in etiopathogenesis and also suggests linkages between these three conditions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4478-4499"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764590","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":"Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-<i>N</i>,<i>N</i>-dimethyltryptamine Analogs in Mice.","authors":"Grant C Glatfelter, Allison A Clark, Natalie G Cavalco, Antonio Landavazo, John S Partilla, Marilyn Naeem, James A Golen, Andrew R Chadeayne, David R Manke, Bruce E Blough, John D McCorvy, Michael H Baumann","doi":"10.1021/acschemneuro.4c00513","DOIUrl":"10.1021/acschemneuro.4c00513","url":null,"abstract":"<p><p>5-methoxy-<i>N</i>,<i>N</i>-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its <i>N</i>-alkyl, <i>N</i>-allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT_2A) and 1A receptors (5-HT_1A), and 3) to examine the influence of 5-HT_1A on 5-HT_2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT_2A and 5-HT_1A. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED₅₀ range = 0.2-1.8 mg/kg) and maximal effects (<i>E</i>_max range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED₅₀ range = 3.2-20.6 mg/kg). 5-HT_2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT_1A antagonist pretreatment enhanced HTRs. In general, <i>N</i>,<i>N</i>-dialkyl and <i>N</i>-isopropyl derivatives displayed HTR activity, while the <i>N</i>-methyl, <i>N</i>-ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT_1A unmasked latent HTR activity for the <i>N</i>-ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT_1A agonist activity can dampen 5-HT_2A-mediated HTRs. Suppression of 5-HT_2A-mediated HTRs by 5-HT_1A only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT_1A agonism in modulating acute psychoactive effects of 5-HT_2A agonists.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4458-4477"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783339","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":"Kratom Alkaloids for the Treatment of Alcohol Use Disorder.","authors":"Joydip Das","doi":"10.1021/acschemneuro.4c00675","DOIUrl":"10.1021/acschemneuro.4c00675","url":null,"abstract":"<p><p>Alcohol use disorder (AUD) accounts for nearly 4.7% of all deaths and imposes a huge economic burden on society. Despite the magnitude of the problem, only a few Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved drugs are currently available for AUD treatment. Despite being efficacious, these drugs are not without problems, adverse effects being a major issue. That combined with medication adherence and compliance problems, the discovery of new drugs is imperative. Kratom (<i>Mitragyna speciosa</i>) alkaloids and some of their semisynthetic derivatives reduce alcohol intake and alcohol-induced withdrawal symptoms in animal models. These compounds act as G-protein-biased ligands at the μ-, δ-, and κ-opioid receptors, and their effect in reducing alcohol intake is mediated through the δ-opioid receptor. This article provides a critical overview of recent preclinical studies involving kratom alkaloids for AUD treatment, with a particular focus on the pharmacology and medicinal chemistry of these alkaloids. FDA/EMA approved drugs, repurposed drugs, and plant-based compounds for the treatment of AUD are briefly mentioned. Finally, important caveats and future research directions on this topic are discussed.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4352-4359"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749421","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 \"Design, Synthesis, and Activity of an α-Conotoxin LtIA Fluorescent Analogue\".","authors":"Yishuai Yang, Yao Tan, Dongting Zhangsun, Xiaopeng Zhu, Sulan Luo","doi":"10.1021/acschemneuro.4c00776","DOIUrl":"10.1021/acschemneuro.4c00776","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4591"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778682","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":"Neurochemical and Morphological Comparisons of Motor Nerve Organoids and Spinal-Cord Explants.","authors":"Shannon E Murphy, Amanda C Sullivan-Weiss, Chen H Sirois, Stanislav S Rubakhin, Hyunjoon Kong, Martha U Gillette, Jonathan V Sweedler","doi":"10.1021/acschemneuro.4c00625","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00625","url":null,"abstract":"<p><p>Organoids are multicellular structures formed <i>in vitro</i> from populations of individual cells allowing modeling of structural and functional aspects of organs and tissues in normal and diseased states. They offer unique opportunities to model and treat disease. Using a mouse embryonic stem cell line, we have cultured organoids that express markers of spinal cord motor neurons as well as motor neurons found within the peripheral nervous system. The morphology and select neurotransmitter content of the organoids and spinal cord explants were compared at different developmental time points. We found indications of maturation in the organoids over time, mirrored by similar trends in the spinal cord explants. Although the organoids contained the same neurotransmitters as the spinal cord explants, the developmental changes of these neurotransmitter levels were less marked in organoids. Given these differences, further work is required to optimize organoid growth conditions to better reproduce <i>in vivo</i> models when using organoids to study development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845266","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":"Psychedelics and Entactogens: Call for Papers.","authors":"Craig W Lindsley, Jacob M Hooker, Kelly Chibale, Christa E Müller, Squire J Booker","doi":"10.1021/acschemneuro.4c00773","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00773","url":null,"abstract":"","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"15 24","pages":"4337-4338"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845268","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}