ACS Chemical Neuroscience最新文献

{"title":"The Neuroprotective Effects of the Crinoid Natural Compound Rhodoptilometrin in Parkinson's Disease Experimental Models: Implications for ER Stress and Autophagy Modulation.","authors":"Zhi-Hong Wen, Ya-Jen Chiu, San-Nan Yang, Bo-Lin Guo, Chien-Wei Feng, Jimmy Ming-Jung Chunag, Nan-Fu Chen, Wu-Fu Chen","doi":"10.1021/acschemneuro.5c00087","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00087","url":null,"abstract":"<p><p>The pathogenesis of Parkinson's disease (PD) involves cellular processes such as endoplasmic reticulum (ER) stress, unfolded protein response, autophagy imbalance, and apoptosis, and identifying drugs that can regulate these molecular mechanisms may be a potential therapeutic strategy for PD. This study aimed to investigate the potential neuroprotective effects of the marine crinoid-derived natural compound (+)-rhodoptilometrin (RDM). We utilized an <i>in vitro</i> PD experimental model and conducted a biochemical analysis to investigate its potential neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced toxicity. We also examined its underlying molecular mechanisms, confirmed using the autophagy inhibitor 3-methyladenine. We utilized an <i>in vivo</i> PD model to evaluate motor function and verified the therapeutic effectiveness of the RDM. RDM effectively inhibited apoptosis, reduced ER stress, and enhanced the viability and autophagy of 6-OHDA-induced SH-SY5Y cells. This was evidenced by reductions in GRP78, p-eIF2α/eIF2α, XBP-1s, and C/EBP homologous protein levels alongside enhancements in LC3-related autophagy pathways. <i>In vivo</i> experiments using zebrafish also showed that RDM significantly attenuated the decrease in locomotor activity caused by 6-OHDA, concurrently alleviating GRP78-related ER stress and promoting antiapoptotic BCL2 expression. These findings indicate that RDM exerted neuroprotective effects by attenuating apoptosis, alleviating ER stress, and promoting autophagy pathways. RDM may be a promising antineurodegenerative drug.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264755","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":"https://doi.org/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":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-10","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":"Neurochemical, Neurocircuitry, and Psychopathological Mechanisms of PTSD: Emerging Pharmacotherapies and Clinical Perspectives.","authors":"Santosh Kumar Prajapati, Shreyasi Majumdar, Snehapriya Murari, Kirti MachhindraVadak, Sairam Krishnamurthy","doi":"10.1021/acschemneuro.5c00335","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00335","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition triggered by exposure to traumatic events, with complex neurobiological anomalies that remain incompletely understood. This review aims to comprehensively explore the neurocircuitry, neurochemical dysregulation, and emerging pharmacological targets associated with PTSD, offering a consolidated framework for developing more effective treatments. Particular emphasis is employed on the role of the hypothalamic-pituitary-adrenal (HPA) axis, monoamines, glutamate, GABAergic, and the orexinergic system, as well as emerging therapeutic agents such as 3,4-methylenedioxymethamphetamine (MDMA), ketamine, suvorexant, and cannabinoid modulators. Psychotherapeutic approaches including cognitive-behavioral therapy (CBT) and prolonged exposure therapy are also discussed in the context of their neurobiological effects. Articles were identified through a structured search in PubMed, Scopus, and Google Scholar, focusing on English-language publications from 1950 to 2025. Inclusion criteria encompassed original research, clinical trials, and reviews relevant to PTSD mechanisms and treatment. By integrating recent findings, this review advances the understanding of PTSD pathophysiology and highlights potential avenues for targeted, personalized therapies, thereby contributing to clinical and translational research in neuropsychiatry.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264753","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":"Structural Changes of Amyloid β-Protein Fibrils on Neuronal Cells.","authors":"Yuto Kado, Kenichi Kawano, Marie Nishikawa, Atsushi Tanaka, Yoshiaki Yano, Masaru Hoshino, Katsumi Matsuzaki","doi":"10.1021/acschemneuro.5c00064","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00064","url":null,"abstract":"<p><p>The abnormal aggregation of amyloid β-protein (Aβ) and resultant neuronal damage are central to the pathogenesis of Alzheimer's disease. Accumulating evidence suggests that neuronal cell membranes play a pivotal role in Aβ self-aggregation. We have shown that fibrils formed by Aβ-(1-40) and Aβ-(1-42) on GM1-containing model membranes (M-fibrils) as well as on neuronal cell membranes (C-fibrils) are more toxic compared with fibrils formed in water (W-fibrils), and that Aβ-(1-40) M-fibrils contain both in-register parallel and 2-residue-shifted antiparallel β-sheets. However, structural information on C-fibrils is lacking. In this study, structural changes of Aβ fibrils on living neuronal cells were detected by Fourier-transform infrared attenuated total reflection spectroscopy. Early Aβ-(1-40) C-fibrils contained antiparallel β-sheet structures, which changed to parallel β-sheet structures similar to W-fibrils as the fibril deposition proceeded. Pulse-chase experiments using two fluorescent-labeled Aβs suggested that these structural transitions occurred continuously from the existing fibrils. Considering the fact that Aβ fibrils start to form on the cell surface and extend into the aqueous phase, such environmental changes around fibrils may be coupled with structural alterations. In contrast, Aβ-(1-42) C-fibrils retained their antiparallel β-sheet structures. For both Aβ-(1-40) and Aβ-(1-42), cell viability continued to decrease even during the structural alterations of Aβ-(1-40), indicating that the antiparallel β-sheet-containing fibrils attaching to the cell surface were responsible for the lasting cytotoxicity. Thus, the antiparallel β-sheet-containing early fibrils are a promising target for anti-Aβ therapy.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264754","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":"Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery.","authors":"Noah Nathan Kochen, Marguerite Murray, Sophia Zafari, Nagamani Vunnam, Elly E Liao, Lihsia Chen, Anthony R Braun, Jonathan N Sachs","doi":"10.1021/acschemneuro.5c00266","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00266","url":null,"abstract":"<p><p>Pathological aggregates of TDP-43 are implicated in Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. While therapeutic efforts have traditionally focused on mitigating end-stage TDP-43 aggregation, recent evidence highlights an upstream and potentially targetable event: the loss of functional nuclear TDP-43 multimers due to disrupted N-terminal domain (NTD) interactions. To address this, we developed fluorescence lifetime (FLT)-based FRET biosensors to monitor TDP-43 multimerization in living cells that couple a full-length TDP-43 FLT-FRET biosensor screen with an NTD-deletion counter screen, forming the foundation of a novel high-throughput screening (HTS) platform. Screening the 2682 compound FDA-approved Selleck library, we identified the small molecule ketoconazole, which stabilizes functional nuclear TDP-43 multimers in an NTD-dependent manner with low micromolar potency. Ketoconazole rescues TDP-43 mislocalization and aggregation, restores SREBP2 mRNA levels under TDP-43 overexpression, improves neuronal health, and partially restores motor function in a TDP-43 <i>C. elegans</i> model. These findings establish both the biosensors and the HTS platform as innovative tools for TDP-43 drug discovery and support an exciting translational approach for targeting TDP-43 proteinopathies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264752","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 KV7.2/3 Channel Activators Exhibit Superior Toxicity and Metabolic Profiles to Flupirtine and Demonstrate Promising In Vivo Analgesic Effects","authors":"Frieda-Marie Bartz,&nbsp;Kinga Sałat,&nbsp;Katarzyna Urbańska,&nbsp;Jana Lemke,&nbsp;Pascal Rosendahl,&nbsp;Louis Schmidt,&nbsp;Lukas Schulig,&nbsp;Ulrike Garscha,&nbsp;Andreas Link and Patrick J. Bednarski*,&nbsp;","doi":"10.1021/acschemneuro.5c0027810.1021/acschemneuro.5c00278","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00278https://doi.org/10.1021/acschemneuro.5c00278","url":null,"abstract":"<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":"16 12","pages":"2322–2333 2322–2333"},"PeriodicalIF":4.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305917","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":"Alzheimer’s Disease: A Review of Molecular Mechanisms and Therapeutic Implications by Targeting Sirtuins, Caspases, and GSK-3","authors":"Kalpana Pandya,&nbsp;Krishnashish Roul,&nbsp;Avanish Tripathi,&nbsp;Sateesh Belemkar,&nbsp;Anshuman Sinha,&nbsp;Meryem Erol and Devendra Kumar*,&nbsp;","doi":"10.1021/acschemneuro.5c0020710.1021/acschemneuro.5c00207","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00207https://doi.org/10.1021/acschemneuro.5c00207","url":null,"abstract":"<p >Alzheimer’s disease (AD) is a neurodegenerative disease with a significant impact on global public health. The primary hallmarks of the disease included amyloid-beta peptide (Aβ) deposition, neurofibrillary tangles (NFT), and synaptic loss. Sirtuins, a group of NAD⁺-dependent deacetylase enzymes, are key regulators of AD pathogenesis. SIRT1, a member of sirtuins, has been identified to possess neuroprotective properties. Thus, its promising enhancers are included. Further, SIRT2 promising inhibitors are reviewed for therapeutic efficacy. The extrinsic and intrinsic apoptotic pathways of caspases are mediated by CD95 and DNA damage. The promising inhibitors Q-VD-OPh and minocycline are found to be specific for caspase-7 and caspase-3, respectively. Primarily, glycogen synthase kinase-3β (GSK-3β) is found to be involved in the generation of phosphorylated tau. The promising GSK-3 inhibitor included the COB-187 (IC₅₀ = 370 nM) and maleimide-derivative (compound 33, IC₅₀ = 0.09 μM). This review highlights the molecular mechanisms of sirtuin, caspase, and GSK-3 in the pathophysiology of AD. Further, promising modulators specific to these targets are described.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 12","pages":"2178–2195 2178–2195"},"PeriodicalIF":4.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305659","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":"Alzheimer's Disease: A Review of Molecular Mechanisms and Therapeutic Implications by Targeting Sirtuins, Caspases, and GSK-3.","authors":"Kalpana Pandya, Krishnashish Roul, Avanish Tripathi, Sateesh Belemkar, Anshuman Sinha, Meryem Erol, Devendra Kumar","doi":"10.1021/acschemneuro.5c00207","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00207","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease with a significant impact on global public health. The primary hallmarks of the disease included amyloid-beta peptide (Aβ) deposition, neurofibrillary tangles (NFT), and synaptic loss. Sirtuins, a group of NAD⁺-dependent deacetylase enzymes, are key regulators of AD pathogenesis. SIRT1, a member of sirtuins, has been identified to possess neuroprotective properties. Thus, its promising enhancers are included. Further, SIRT2 promising inhibitors are reviewed for therapeutic efficacy. The extrinsic and intrinsic apoptotic pathways of caspases are mediated by CD95 and DNA damage. The promising inhibitors Q-VD-OPh and minocycline are found to be specific for caspase-7 and caspase-3, respectively. Primarily, glycogen synthase kinase-3β (GSK-3β) is found to be involved in the generation of phosphorylated tau. The promising GSK-3 inhibitor included the COB-187 (IC₅₀ = 370 nM) and maleimide-derivative (compound 33, IC₅₀ = 0.09 μM). This review highlights the molecular mechanisms of sirtuin, caspase, and GSK-3 in the pathophysiology of AD. Further, promising modulators specific to these targets are described.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256627","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":"An Integrative Analysis of Metagenomic and Metabolomic Profiling Reveals Gut Microbiome Dysbiosis and Metabolic Alterations in ALS: Potential Biomarkers and Therapeutic Insights.","authors":"Priyanka Gautam, Rahul Yadav, Ranjeet Kumar Vishwakarma, Shashi Shekhar, Abhishek Pathak, Chandan Singh","doi":"10.1021/acschemneuro.5c00254","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00254","url":null,"abstract":"<p><p>ALS is a severe neurodegenerative disorder characterized by motor neuron degeneration, gut dysbiosis, immune dysregulation, and metabolic disturbances. In this study, shotgun metagenomics and ¹H nuclear magnetic resonance (NMR)-based metabolomics were employed to investigate the altered gut microbiome and metabolite profiles in individuals with ALS, household controls (HCs), and nonhousehold controls (NHCs). The principal component analysis (PCA) explained 33% of the variance, and the partial least-squares discriminant analysis (PLS-DA) model demonstrate <i>R</i>² and <i>Q</i>² values of 0.97 and 0.84, respectively, indicating an adequate model fit. The relative bacterial abundance was 99.34% in the ALS group and 98.94% in the HC group. Among the ten identified genera, <i>Bifidobacterium</i>, <i>Lactobacillus</i>, and <i>Enterococcus</i> were more prevalent in ALS individuals, while <i>Lactiplantibacillus</i> and <i>Klebsiella</i> were more abundant in the HC group. We identified 70 metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), carbohydrates, and aromatic compounds, using NMR. Orthogonal partial least-squares discriminant analysis (O-PLS-DA) explained 15.8% of the variance, with a clear separation between the ALS and HC groups. Univariate receiver operating characteristic (ROC) analysis identified three fecal metabolites with AUC values above 0.70, including butyrate (0.798), propionate (0.727), and citrate (0.719). These metabolites may serve as potential biomarkers for ALS. The statistical model for metabolic pathway analysis revealed interconnected pathways, highlighting the complexity of metabolic dysregulation, as well as potential microbial and metabolic biomarkers in ALS. These results highlight the role of gut microbiome alterations in ALS and suggest potential avenues for therapeutic intervention.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245190","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":"https://doi.org/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":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-06","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}