ACS Chemical Neuroscience最新文献

{"title":"Cracking Amyloid Toxicity: Naringin Rescues Neuronal Cells in a Minimal Alzheimer's Model.","authors":"Emre Korkmaz, Jülide Secerli, Hakan Erdoğan, Merve Güdül Bacanlı","doi":"10.1021/acschemneuro.5c00410","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00410","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid plaque accumulation, and neuronal dysfunction. The diphenylalanine (Phe-Phe) dipeptide, a core self-assembling motif of amyloid-β (Aβ) peptides, has recently gained attention as a simplified and cost-effective model for mimicking amyloid aggregation <i>in vitro</i>. In this study, we established a Phe-Phe-induced AD model in SH-SY5Y neuroblastoma cells to investigate the effects of naringin (NAR), a <i>Citrus</i>-derived flavanone glycoside known for its antioxidative and anti-inflammatory properties, on AD. Following Phe-Phe exposure, cells were treated with NAR at subcytotoxic concentrations. Multiple end points including cytotoxicity, reactive oxygen species (ROS) generation, DNA damage (Comet assay), AD-related biomarkers (acetylcholinesterase (AChE), amyloid beta (Aβ), amyloid precursor protein (APP), tau protein), cytokine levels, caspase activation, and apoptosis were evaluated. NAR treatment significantly attenuated Phe-Phe-induced ROS production, genotoxicity, and inflammatory responses, while reducing apoptotic cell death and restoring biomarker levels toward physiological norms. These findings demonstrate that NAR exerts multitargeted neuroprotective effects and suggest its therapeutic potential in AD. Additionally, the Phe-Phe model was validated as a reproducible and biologically relevant <i>in vitro</i> system for screening anti-amyloid agents.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935615","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":"Progress toward Multianalyte Neurochemical Detection: Techniques and Applications.","authors":"Kalynn M Turner, Jenna M Berger, Leslie A Sombers","doi":"10.1021/acschemneuro.5c00286","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00286","url":null,"abstract":"<p><p>Brain function is shaped by the coordinated activity of billions of neurons. The neurotransmitters and neuromodulators released from these neurons work together to modulate circuit function and, ultimately, behavior. Electroanalytical technologies are particularly valuable for simultaneous detection of multiple biomolecular targets in a single assay. However, to date, most studies that have investigated rapid neurochemical dynamics have targeted a single analyte at a time─usually dopamine. Information on how chemical signals fluctuate relative to one another is largely limited to assays that use electrode arrays (with one target per recording site), while multianalyte detection at single electrodes remains relatively under-developed. This review provides a comprehensive discussion of the strengths and weaknesses associated with classic approaches to molecular monitoring in the brain─microdialysis sampling, electroanalytical techniques, and photometric approaches─and key advances toward multianalyte sensing at single recording sites. The codetection of multiple analytes at the same space and time promises to provide an entirely new perspective on brain function (and dysfunction) that can be exploited to inform on the development of improved therapeutic strategies to treat neurological disorders, broadly speaking.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935684","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":"7T GluCEST in Discriminating Gliomas with Diverse Invasiveness Degrees and Its Association with Invasion Indices","authors":"Shuyi Sun,&nbsp;Lingfeng Lai,&nbsp;Mingmin Wu,&nbsp;Caiyu Zhuang,&nbsp;Yiru Hu,&nbsp;Beibei Chen,&nbsp;Xinhui Zheng,&nbsp;Yue Chen,&nbsp;Jiaji Mao,&nbsp;Jitian Guan* and Zhuozhi Dai*,&nbsp;","doi":"10.1021/acschemneuro.5c00048","DOIUrl":"10.1021/acschemneuro.5c00048","url":null,"abstract":"<p >This study aimed to evaluate and compare the effectiveness of glutamate chemical exchange saturation transfer (GluCEST) with that of proton MR spectroscopy (¹H-MRS) and other conventional magnetic resonance imaging in distinguishing gliomas of different invasiveness and exploring their correlation with the expression of Ki-67. Twenty-four adult male Sprague–Dawley rats were included and randomly divided into three subgroups of the gliomas: C6, 9L, and F98. Sequential GluCEST, ¹H-MRS, diffusion weighted imaging, and T2-weighted imaging scans were performed on the intracranial glioma-bearing rats using a 7.0T animal MRI scanner 10 days after tumor induction. Tumor tissue was analyzed histopathologically after the imaging protocol, with Ki-67 labeling index (LI), glial fibrillary acidic protein (GFAP), microvessel density (MVD) indicated by Cluster of Differentiation 34 (CD34), and conventional hematoxylin and eosin staining measured for each glioma model. The diagnostic efficacy of each imaging modality was calculated. Increased tumor GluCEST contrast was found to be associated with more aggressive gliomas. In comparison to various imaging techniques, GluCEST demonstrated the highest diagnostic efficacy. More importantly, GluCEST contrast demonstrated a strong positive correlation with the tumor volume, Ki-67 LI, and MVD. In conclusion, 7T GluCEST imaging enables noninvasive visualization of the glutamate microenvironment of gliomas, thereby offering a reliable and promising imaging approach for differentiating the invasiveness of gliomas.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 18","pages":"3472–3480"},"PeriodicalIF":3.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935680","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":"Investigating Curvature Sensing by the Nt17 Domain of Huntingtin Protein","authors":"Neha Nanajkar,&nbsp;Abhilash Sahoo,&nbsp;Shelli L. Frey and Silvina Matysiak*,&nbsp;","doi":"10.1021/acschemneuro.5c00298","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00298","url":null,"abstract":"<p >Nt17, the N-terminal domain of the huntingtin protein (htt), has garnered significant attention for its role in htt’s membrane binding and aggregation processes. Previous studies have identified a nuclear export sequence within the Nt17 domain and demonstrated its localization at various cellular organelles. Recent evidence suggests that, like other amphipathic helices, Nt17 can sense and preferentially bind to curved membranes. Gaining deeper insight into this behavior is essential to fully understand the function of this domain. In this study, we combine coarse-grained molecular dynamics simulations with circular dichroism (CD) spectroscopy to investigate the mechanism behind Nt17’s curvature sensing. We generated a unique hemispherical-planar membrane model, where 36% of the upper leaflet surface is curved, allowing us to evaluate Nt17’s binding preferences. Our findings show that Nt17 exhibits a strong preference for curved regions, with approximately 78 ± 7% of peptides binding to these areas. This interaction is primarily mediated by the terminal Phe residues, indicating that Nt17’s curvature sensing is driven by its ability to detect lipid packing defects. Furthermore, Nt17 not only senses these defects but also amplifies them by coalescing into smaller pockets. Mutating the Phe residues to methionine, a smaller hydrophobic residue, significantly reduces Nt17’s curvature sensitivity, resulting in equal binding to both curved and planar regions. CD spectroscopy corroborates these results, showing that Nt17 binds more strongly to highly curved small unilamellar vesicles (SUVs) compared to larger, less curved large unilamellar vesicles (LUVs).</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3282–3291"},"PeriodicalIF":3.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928950","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":"Design, Synthesis, and Biological Evaluation of Novel Heteroaryl, Squaramide, and Indolcarboxamide Derivatives as Formyl Peptide Receptor 2 Agonists to Target Neuroinflammation","authors":"Fabio Francavilla,&nbsp;Daniele Vitone,&nbsp;Igor A. Schepetkin,&nbsp;Lilya N. Kirpotina,&nbsp;Antonio Carrieri,&nbsp;Leonardo Brunetti,&nbsp;Imane Ghafir El Idrissi,&nbsp;Maria Grazia Perrone,&nbsp;Jakub Kosma Frydrych,&nbsp;Ewa Trojan,&nbsp;Mark T. Quinn,&nbsp;Agnieszka Basta-Kaim,&nbsp;Enza Lacivita* and Marcello Leopoldo,&nbsp;","doi":"10.1021/acschemneuro.5c00308","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00308","url":null,"abstract":"<p >Recent research reveals Formyl Peptide Receptor 2 (FPR2) as a relevant G Protein-Coupled Receptor involved in the resolution phase of inflammation. Therefore, FPR2 agonists are promising agents to tackle neuroinflammatory-based diseases, such as Alzheimer’s Disease or Autism Spectrum Disorder. Here, we describe the synthesis and biological evaluation of novel FPR2 agonists designed through the bioisosteric replacement of the phenyl urea function in the potent FPR2 agonist (S)-1-(3-(4-cyanophenyl)-1-(indolin-1-yl)-1-oxopropan-2-yl)-3-(4-fluorophenyl)urea (<b>5</b>), obtaining novel heteroaryl, squaramide, and indolcarboxamide derivatives. The structural modification had a profound effect on FPR2 agonist potency, metabolic stability, aqueous solubility, and cell permeability, resulting in compounds with distinct profiles. Computational studies have shown that the new compounds exhibit the same contacts with key amino acids in the binding site as the starting FPR2 agonist <b>5</b>. However, subtle differences in the orientation or the presence and position of heteroatoms in the selected scaffolds translate to substantial differences in FPR2 potency. Among the new compounds, (<i>S</i>)-<b>9a</b>, (<i>S</i>)-<b>12a</b>, and (<i>S</i>)-<b>16b</b> demonstrated neuroprotective, anti-inflammatory, and pro-resolving properties in mouse primary microglial cells, stimulated with lipopolysaccharide. Although the replacement of the phenyl urea with different scaffolds did not lead to the identification of a bioisostere, compounds (<i>S</i>)-<b>9a</b>, (<i>S</i>)-<b>12a</b>, and (<i>S</i>)-<b>16b</b> represent a starting point for the development of a new class of FPR2 agonists.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 17","pages":"3292–3311"},"PeriodicalIF":3.9,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928941","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 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}