ACS Chemical Neuroscience最新文献_第10页

Interplay between Copper, Phosphatidylserine, and α-Synuclein Suggests a Link between Copper Homeostasis and Synaptic Vesicle Cycling. 铜、磷脂酰丝氨酸和α-突触核蛋白之间的相互作用表明铜平衡与突触小泡循环之间存在联系

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-16 DOI: 10.1021/acschemneuro.4c00280

Xiangyu Teng, Ewelina Stefaniak, Keith R Willison, Liming Ying

{"title":"Interplay between Copper, Phosphatidylserine, and α-Synuclein Suggests a Link between Copper Homeostasis and Synaptic Vesicle Cycling.","authors":"Xiangyu Teng, Ewelina Stefaniak, Keith R Willison, Liming Ying","doi":"10.1021/acschemneuro.4c00280","DOIUrl":"10.1021/acschemneuro.4c00280","url":null,"abstract":"Copper homeostasis is critical to the functioning of the brain, and its breakdown is linked with many brain diseases. Copper is also known to interact with the negatively charged lipid, phosphatidylserine (PS), as well as α-synuclein, an aggregation-prone protein enriched in the synapse, which plays a role in synaptic vesicle docking and fusion. However, the interplay between copper, PS lipid, and α-synuclein is not known. Herein, we report a detailed and predominantly kinetic study of the interactions among these three components pertinent to copper homeostasis and neurotransmission. We found that synaptic vesicle-mimicking small unilamellar vesicles (SUVs) can sequester any excess free Cu2+ within milliseconds, and bound Cu2+ on SUVs can be reduced to Cu+ by GSH at a nearly constant rate under physiological conditions. Moreover, we revealed that SUV-bound Cu2+ does not affect the binding between wild-type α-synuclein and SUVs but affect that between N-terminal acetylated α-synuclein and SUVs. In contrast, Cu2+ can effectively displace both types of α-synuclein from the vesicles. Our results suggest that synaptic vesicles may mediate copper transfer in the brain, while copper could participate in synaptic vesicle docking to the plasma membrane via its regulation of the interaction between α-synuclein and synaptic vesicle.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11311125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625269","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}

引用次数: 0

Correction to "Menthol-Modified Quercetin Liposomes with Brain-Targeting Function for the Treatment of Senescent Alzheimer's Disease". 具有脑靶向功能的薄荷改性槲皮素脂质体用于治疗老年性阿尔茨海默病》的更正。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-10 DOI: 10.1021/acschemneuro.4c00398

Wan-Ying Liu, Yang Yu, Juan Zang, Yang Liu, Feng-Rui Li, Lu Zhang, Rui-Bo Guo, Liang Kong, Ling-Yue Ma, Xue-Tao Li

引用次数: 0

Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents. 芬太尼支架的结构-活性关系：鉴定作为潜在阿片类药物过量逆转剂的拮抗剂。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-12 DOI: 10.1021/acschemneuro.4c00203

Jessica P Anand, Sierra C Moore, Emma E Dixon, Carmelita M Perrien Naccarato, Joshua L West, Lennon J Delong, Emily Burgess, Jack J Twarozynski, John R Traynor

{"title":"Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents.","authors":"Jessica P Anand, Sierra C Moore, Emma E Dixon, Carmelita M Perrien Naccarato, Joshua L West, Lennon J Delong, Emily Burgess, Jack J Twarozynski, John R Traynor","doi":"10.1021/acschemneuro.4c00203","DOIUrl":"10.1021/acschemneuro.4c00203","url":null,"abstract":"Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588884","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}

引用次数: 0

TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction. TDP-43 通过直接分子相互作用延迟纤维成熟，从而促进淀粉样蛋白-β的毒性。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-29 DOI: 10.1021/acschemneuro.4c00334

Adam J Gatch, Feng Ding

{"title":"TDP-43 Promotes Amyloid-Beta Toxicity by Delaying Fibril Maturation via Direct Molecular Interaction.","authors":"Adam J Gatch, Feng Ding","doi":"10.1021/acschemneuro.4c00334","DOIUrl":"10.1021/acschemneuro.4c00334","url":null,"abstract":"Amyloid-β (Aβ) is a peptide that undergoes self-assembly into amyloid fibrils, which compose the hallmark plaques observed in Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) is a protein with mislocalization and aggregation implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases. Recent work suggests that TDP-43 may interact with Aβ, inhibiting the formation of amyloid fibrils and worsening AD pathology, but the molecular details of their interaction remain unknown. Using all-atom discrete molecular dynamics simulations, we systematically investigated the direct molecular interaction between Aβ and TDP-43. We found that Aβ monomers were able to bind near the flexible nuclear localization sequence of the N-terminal domain (NTD) of TDP-43, adopting β-sheet rich conformations that were promoted by the interaction. Furthermore, Aβ associated with the nucleic acid binding interface of the tandem RNA recognition motifs of TDP-43 via electrostatic interactions. Using the computational peptide array method, we found the strongest C-terminal domain interaction with Aβ to be within the amyloidogenic core region of TDP-43. With experimental evidence suggesting that the NTD is necessary for inhibiting Aβ fibril growth, we also simulated the NTD with an Aβ40 fibril seed. We found that the NTD was able to strongly bind the elongation surface of the fibril seed via extensive hydrogen bonding and could also diffuse along the lateral surface via electrostatic interactions. Our results suggest that TDP-43 binding to the elongation surface, thereby sterically blocking Aβ monomer addition, is responsible for the experimentally observed inhibition of fibril growth. We conclude that TDP-43 may promote Aβ toxicity by stabilizing the oligomeric state and kinetically delaying fibril maturation.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786410","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}

引用次数: 0

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration. 多谷氨酰胺（PolyQ）疾病：导航神经退行性疾病。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-12 DOI: 10.1021/acschemneuro.4c00184

Rumiana Tenchov, Janet M Sasso, Qiongqiong Angela Zhou

{"title":"Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration.","authors":"Rumiana Tenchov, Janet M Sasso, Qiongqiong Angela Zhou","doi":"10.1021/acschemneuro.4c00184","DOIUrl":"10.1021/acschemneuro.4c00184","url":null,"abstract":"Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally expanded polyglutamine tract. A total of nine polyQ disorders have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). The diseases of this class are each considered rare, yet polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. While each subtype of polyQ diseases has its own causative gene, certain pathologic molecular attributes have been implicated in virtually all of the polyQ diseases, including protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Although animal models of polyQ disease are available helping to understand their pathogenesis and access disease-modifying therapies, there is neither a cure nor prevention for these diseases, with only symptomatic treatments available. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in the class of polyQ diseases. We examine the publication landscape in the area in effort to provide insights into current knowledge advances and developments. We review the most discussed concepts and assess the strategies to combat these diseases. Finally, we inspect clinical applications of products against polyQ diseases with their development pipelines. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding the class of polyQ diseases, to outline challenges, and evaluate growth opportunities to further efforts in combating the diseases.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11311141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597895","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}

引用次数: 0

Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson's Disease. 设计、合成和评估具有多巴胺能和神经保护活性的新型帕金森病共轭分子。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-11 DOI: 10.1021/acschemneuro.4c00169

Diego Ploper, Agustín O Pernicone, Rodrigo H Tomas-Grau, Verónica E Manzano, Sergio B Socías, María Del Milagro Teran, Valentina Budeguer Isa, Bernardo Sosa-Padilla, Florencia González-Lizárraga, César L Avila, María Laura Guayán, Silvina Chaves, Hernán Cruz, Esteban Vera Pingitore, Oscar Varela, Rosana Chehín

{"title":"Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson's Disease.","authors":"Diego Ploper, Agustín O Pernicone, Rodrigo H Tomas-Grau, Verónica E Manzano, Sergio B Socías, María Del Milagro Teran, Valentina Budeguer Isa, Bernardo Sosa-Padilla, Florencia González-Lizárraga, César L Avila, María Laura Guayán, Silvina Chaves, Hernán Cruz, Esteban Vera Pingitore, Oscar Varela, Rosana Chehín","doi":"10.1021/acschemneuro.4c00169","DOIUrl":"10.1021/acschemneuro.4c00169","url":null,"abstract":"The escalating prevalence of Parkinson's disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard l-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9, a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a nonantibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions and sustained antioxidant and anti-inflammatory properties of the tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic α-synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed light onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588882","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}

引用次数: 0

Applying Spatial Metabolomics To Investigate Age- and Drug-Induced Neurochemical Changes. 应用空间代谢组学研究年龄和药物引起的神经化学变化

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-29 DOI: 10.1021/acschemneuro.4c00199

Theodosia Vallianatou, Tina B Angerer, Ibrahim Kaya, Anna Nilsson, Reza Shariatgorji, Per Svenningsson, Per E Andrén

{"title":"Applying Spatial Metabolomics To Investigate Age- and Drug-Induced Neurochemical Changes.","authors":"Theodosia Vallianatou, Tina B Angerer, Ibrahim Kaya, Anna Nilsson, Reza Shariatgorji, Per Svenningsson, Per E Andrén","doi":"10.1021/acschemneuro.4c00199","DOIUrl":"10.1021/acschemneuro.4c00199","url":null,"abstract":"In an era when population aging is increasing the burden of neurodegenerative conditions, deciphering the mechanisms underlying brain senescence is more important than ever. Here, we present a spatial metabolomics analysis of age-induced neurochemical alterations in the mouse brain using negative ionization mode mass spectrometry imaging. The age-dependent effects of the acetylcholinesterase inhibitor tacrine were simultaneously examined. For ultrahigh mass resolution analysis, we utilized a Fourier-transform ion cyclotron resonance spectrometer. To complement this, a trapped ion mobility spectrometry time-of-flight analyzer provided high speed and lateral resolution. The chosen approach facilitated the detection and identification of a wide range of metabolites, from amino acids to sphingolipids. We reported significant, age-dependent alterations in brain lipids which were most evident for sulfatides and lysophosphatidic acids. Sulfatide species, which are mainly localized to white matter, either increased or decreased with age, depending on the carbon chain length and hydroxylation stage. Lysophosphatidic acids were found to decrease with age in the detailed cortical and hippocampal subregions. An age-dependent increase in the glutamine/glutamate ratio, an indicator of glia-neuron interconnection and neurotoxicity, was detected after tacrine administration. The presented metabolic mapping approach was able to provide visualizations of the lipid signaling and neurotransmission alterations induced by early aging and can thus be beneficial to further elucidating age-related neurochemical pathways.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11311129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786409","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}

引用次数: 0

Red-Light-Photosensitized Tyrosine 10 Nitration of β-Amyloid_1-42 Diverts the Protein from Forming Toxic Aggregates. β-淀粉样蛋白1-42的红光光敏化酪氨酸10硝化作用可阻止该蛋白形成毒性聚集。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-22 DOI: 10.1021/acschemneuro.4c00284

Sarah Basile, Cristina Parisi, Francesco Bellia, Stefania Zimbone, Giuseppe Arrabito, Daniele Gulli, Bruno Pignataro, Maria Laura Giuffrida, Salvatore Sortino, Agata Copani

{"title":"Red-Light-Photosensitized Tyrosine 10 Nitration of β-Amyloid1-42 Diverts the Protein from Forming Toxic Aggregates.","authors":"Sarah Basile, Cristina Parisi, Francesco Bellia, Stefania Zimbone, Giuseppe Arrabito, Daniele Gulli, Bruno Pignataro, Maria Laura Giuffrida, Salvatore Sortino, Agata Copani","doi":"10.1021/acschemneuro.4c00284","DOIUrl":"10.1021/acschemneuro.4c00284","url":null,"abstract":"Several studies have highlighted the presence of nitration damage following neuroinflammation in Alzheimer's disease (AD). Accordingly, post-transcriptional modifications of β-amyloid (Aβ), including peptide nitration, have been explored as a marker of the disease. However, the implications of Aβ nitration in terms of aggregation propensity and neurotoxicity are still debated. Here, we show new data obtained using a photoactivatable peroxynitrite generator (BPT-NO) to overcome the limitations associated with chemical nitration methods. We found that the photoactivation of BPT-NO with the highly biocompatible red light selectively induces the nitration of tyrosine 10 of freshly solubilized full-length Aβ1-42. Photonitrated Aβ1-42 was, therefore, investigated for aggregation states and functions. It resulted that photonitrated Aβ1-42 did not aggregate into small oligomers but rather self-assembled into large amorphous aggregates. When tested on neuronal-like SH-SY5Y cells and microglial C57BL/6 BV2 cells, photonitrated Aβ1-42 showed to be free of neurotoxicity and able to induce phagocytic microglia cells. We propose that light-controlled nitration of the multiple forms in which Aβ occurs (i.e., monomers, oligomers, fibrils) could be a tool to assess in real-time the impact of tyrosine nitration on the amyloidogenic and toxic properties of Aβ1-42.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732766","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}

引用次数: 0

Synthesis and Biological Evaluation of Colchicine─Aryl/Alkyl Amine Hybrids as Potential Noncytotoxic Cholinesterase Inhibitors: Identification of SBN-284 as a Dual Inhibitor of Cholinesterases and NLRP3 Inflammasome. 作为潜在的无细胞毒性胆碱酯酶抑制剂的秋水仙碱-芳基/烷基胺杂交化合物的合成与生物学评价：鉴定 SBN-284 为胆碱酯酶和 NLRP3 炎症体的双重抑制剂。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-07 Epub Date: 2024-07-26 DOI: 10.1021/acschemneuro.4c00153

Chilakala Nagarjuna Reddy, Vijay K Nuthakki, Ankita Sharma, Sumera Malik, Misbah Tabassum, Rajesh Kumar, Sushil Choudhary, Fiza Iqbal, Ziya Tufail, Dilip M Mondhe, Ajay Kumar, Sandip B Bharate

{"title":"Synthesis and Biological Evaluation of Colchicine─Aryl/Alkyl Amine Hybrids as Potential Noncytotoxic Cholinesterase Inhibitors: Identification of SBN-284 as a Dual Inhibitor of Cholinesterases and NLRP3 Inflammasome.","authors":"Chilakala Nagarjuna Reddy, Vijay K Nuthakki, Ankita Sharma, Sumera Malik, Misbah Tabassum, Rajesh Kumar, Sushil Choudhary, Fiza Iqbal, Ziya Tufail, Dilip M Mondhe, Ajay Kumar, Sandip B Bharate","doi":"10.1021/acschemneuro.4c00153","DOIUrl":"10.1021/acschemneuro.4c00153","url":null,"abstract":"Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer's disease by targeting neuroinflammation and cholinesterases. Molecular docking revealed that colchicine's hydrophobic trimethoxyphenyl framework can potentially bind to the peripheral anionic site of cholinesterases. Hybrid structures combining colchicine with aryl/alkyl amines were designed to bind both peripheral and catalytic sites of cholinesterases. We describe here the design, synthesis, and in vitro cytotoxicity evaluation of these colchicine-aryl/alkyl amine hybrids, along with their in silico interactions with the cholinesterase active site gorge. Nontoxic analogs demonstrating strong cholinesterase binding affinity were further evaluated for their anticholinesterase and antineuroinflammatory activities. The colchicine-donepezil hybrid, SBN-284 (3x), inhibited both acetylcholinesterase and butyrylcholinesterase as well as the NLRP3 inflammasome complex at low micromolar concentrations. It achieved this through noncompetitive inhibition, occupying the active site gorge and interacting with both peripheral and catalytic anionic sites of cholinesterases. Analog 3x was shown to cross the blood-brain barrier and exhibited no toxicity to neuronal cells, primary macrophages, or epithelial fR2 cells. These findings highlight the potential of this lead compound for further preclinical investigation as a promising anti-Alzheimer agent.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755500","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}

引用次数: 0

Neuromicrobiology Comes of Age: The Multifaceted Interactions between the Microbiome and the Nervous System 神经微生物学时代的到来：微生物组与神经系统之间的多方面相互作用

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-08-05 DOI: 10.1021/acschemneuro.4c0030710.1021/acschemneuro.4c00307

Ashwarya S. Devason, Christoph A. Thaiss* and Cesar de la Fuente-Nunez*,

引用次数: 0