ACS Chemical Neuroscience最新文献

{"title":"Dysregulated Neurotransmission and the Role of Viruses in Alzheimer's Disease.","authors":"Katherine Bovis, Martha Davies-Branch, Philip J R Day","doi":"10.1021/acschemneuro.4c00763","DOIUrl":"10.1021/acschemneuro.4c00763","url":null,"abstract":"<p><p>The causes of neurodegeneration remain elusive. There is growing evidence linking viral infection to dysregulated neurotransmission as a causative factor in Alzheimer's disease. Studies suggest that viral infection may result in dysregulated glutamatergic and l-arginine/NO neurotransmission that can initiate neurodegeneration and neuroinflammation within AD. This involves viral infection (HIV-1/HSV-1) altering glutamate biosynthesis and receptor activation resulting in excessive influxes of glutamate and subsequent dysregulation of Ca²⁺ influx that all contribute to reduced dendrite growth and tau phosphorylation. For l-arginine/NO neurotransmission, the mechanism derives from the \"protective\" antiviral mechanisms of NO that correlate with pathologies such as β-amyloid peptide accumulation and functional degeneration of hippocampal neurons, respectively. More research is required to underpin the direct mechanisms that viruses might impact to induce specific pathologies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"982-987"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565586","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":"Effect of SSR504734, a Selective Glycine Transporter Type 1 Inhibitor, on Seizure Thresholds, Neurotransmitter Levels, and Inflammatory Markers in Mice.","authors":"Nikola Gapińska, Piotr Wlaź, Elżbieta Wyska, Artur Świerczek, Krzysztof Kamiński, Marcin Jakubiec, Michał Abram, Katarzyna Ciepiela, Gniewomir Latacz, Tymoteusz Słowik, Dawid Krokowski, Łukasz Jarosz, Artur Ciszewski, Katarzyna Socała","doi":"10.1021/acschemneuro.5c00039","DOIUrl":"10.1021/acschemneuro.5c00039","url":null,"abstract":"<p><p>Studies have revealed that inhibition of glycine transporter type 1 (GlyT1) may provide a balanced regulation between excitation and inhibition in some brain structures and, thereby, modulate seizure activity. Data on the role of GlyT1 in epilepsy are, however, very limited. Here, we examined the effect of SSR504734, a highly selective and reversible GlyT1 inhibitor, on three acute seizure tests in mice. We also evaluated its impact on neurotransmitter levels in the relevant brain structures following seizures, possible adverse effects, and changes in the levels of inflammatory mediators in the serum and liver. In addition, in vivo pharmacokinetic profile and in vitro ADME-Tox properties of SSR504734 were investigated. The results show that SSR504734 significantly increased the threshold for tonic hindlimb extension in the MEST test after acute and repeated treatment but had no influence on seizure thresholds in the 6 Hz and i.v. PTZ seizure tests. SSR504734 did not affect the levels of glutamate, GABA, glycine, or adenosine in brain structures of mice with MES-induced seizures. However, after acute treatment, the concentration of glutamate and adenosine in the brainstem of control animals (i.e., without seizures) decreased. Moreover, SSR504734 increased the levels of inflammatory markers (TNF-α, Il-1β, IL-6, IL-10, and TLR4) in serum. In vivo pharmacokinetic profiling and in vitro ADME-Tox data confirmed suitable drug-like properties of SSR504734, including its notable penetration into brain tissue. However, possible hepatotoxicity at higher doses should be taken into account. Further studies should be considered to better characterize the SSR504734-mediated effects as well as to validate GlyT1 as a potential new molecular target in epilepsy treatment.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1210-1226"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513988","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":"Evaluating the Molecular Interactions between Type 2 Diabetes Mellitus and Parkinson's Disease: Role of Antidiabetic Drugs as Promising Therapeutics.","authors":"Irum Waheed, Talal Sikandri, Sumbal Zaheen, Muhammad Mahtab Aslam Khan Khakwani, Zhaowu An, Tingting Liu, Chaoyang Zhu, Jianshe Wei","doi":"10.1021/acschemneuro.4c00819","DOIUrl":"10.1021/acschemneuro.4c00819","url":null,"abstract":"<p><p>Evidence from previous research demonstrates a relationship between diabetes mellitus (DM) and Parkinson's disease (PD). T2DM is associated with chronic glucose dysregulation, as an etiological factor. It inhibits neuronal function through disrupted insulin signaling and oxidative stress, which ultimately lead to the loss of dopaminergic neurons in the substantia nigra (SN). Interactions between T2DM and PD were analyzed by gene expression, coexpression, and gene set enrichment via NCBI and STRING databases following pathways like KEGG and Reactome. The study identified nine key gene interactions through published literature on different databases and search engines that are involved in the progression of these chronic diseases. Furthermore, some genetic and nongenetic risk factors, gene mutations and environmental factors, are also involved in the progression of T2DM and PD. This review highlights the limitations of currently available drug treatments for these diseases and examines modern therapeutic approaches to address neurodegenerative and metabolic abnormalities. We critically assess the current experimental methodologies aimed at unraveling the pathophysiological mechanisms linking PD and T2DM while addressing the key challenges impeding a comprehensive understanding of the concurrent emergence of these debilitating age-related conditions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"988-999"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555301","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":"Modulation of α-Synuclein Fibrillation and Toxicity by 4-Phenylbutyric Acid.","authors":"Kristos Baffour, Neelima Koti, Tony Nyabayo, Sathvika Balerao, Carissa Sutton, David Johnson, Rishi Patel, Santimukul Santra, Tuhina Banerjee","doi":"10.1021/acschemneuro.4c00709","DOIUrl":"10.1021/acschemneuro.4c00709","url":null,"abstract":"<p><p>The protein misfolding and aggregation of α-synuclein (α-Syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Emerging evidence suggests that 4-phenylbutyrate (PBA) may play a role as a potential chemical chaperone for targeting α-Syn aggregation, but its molecular mechanism remains largely unknown. Using in vitro assays, we demonstrate that PBA treatment alters the pattern of α-Syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K (PK) assays, surface plasmon resonance (SPR), Nile red assays, and cytotoxicity assays indicate that PBA interacts with the extensive hydrophobic contacts of α-Syn oligomers and significantly reduces α-Syn-amyloid-induced toxicity. Furthermore, using thioflavin T-based assays, we elucidated the kinetics of PBA-mediated modulation of α-Syn aggregation, highlighting its role in accelerating the formation of α-Syn amyloid fibrils. Molecular dynamics (MD) simulations suggest PBA's role in the destabilization of the C-terminus in α-Syn oligomers through multiple residue interactions. Collectively, our findings provide compelling evidence for the neuroprotective potential of PBA in targeting protein misfolding and aggregation in PD and suggest an avenue for disease-modifying interventions in neurodegenerative disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1066-1078"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527786","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":"Radiosynthesis, <i>In Vitro</i> Characterization, and <i>In Vivo</i> PET Neuroimaging of [¹⁸F]F-4 for Tau Protein: A First-in-Human PET Study.","authors":"Anton Lindberg, Junchao Tong, Chao Zheng, Andre Mueller, Heiko Kroth, Andrew Stephens, Chester A Mathis, Neil Vasdev","doi":"10.1021/acschemneuro.4c00866","DOIUrl":"10.1021/acschemneuro.4c00866","url":null,"abstract":"<p><p>[¹⁸F]PI-2620 is a promising radiopharmaceutical for positron emission tomography (PET) imaging of both Alzheimer's disease (AD) and non-Alzheimer's disease (non-AD) tauopathies in humans. An array of fluorinated derivatives of the carbazole scaffold of PI-2620 were synthesized and evaluated. <i>In vitro</i> binding assays with [³H]PI-2620 in human tissues with AD, progressive supranuclear palsy, and corticobasal degeneration, combined with <i>in silico</i> predictions of blood-brain barrier permeability, led to the selection and radiosynthesis of [¹⁸F]F-4 as a promising radiotracer. <i>In vivo</i> PET imaging with [¹⁸F]F-4 in healthy rats showed brain uptake and kinetics suitable for neuroimaging, similar to those of [¹⁸F]PI-2620. A first-in-human PET imaging study in a healthy subject as well as a patient with AD, in comparison with [¹⁸F]PI-2620 in the same AD subject, confirmed that [¹⁸F]F-4 is an alternative radiopharmaceutical for imaging tau protein.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1182-1189"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595768","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":"Enhanced Pain Sensitization Induced by Chronic Sleep Deprivation: The Role of Dopamine D2 Receptors-Dependent Homer1a Protein.","authors":"Chao Fu, Peng Wu, Fancan Wu, Wanyou He, Qichen Luo, Hongbin Liang, Hanbing Wang, Yalan Li","doi":"10.1021/acschemneuro.4c00640","DOIUrl":"10.1021/acschemneuro.4c00640","url":null,"abstract":"<p><p>Numerous studies have demonstrated a positive correlation between sleep disorders and hyperalgesia. These sleep disorders adversely affect the descending pain regulatory system. Researchers have extensively studied the midbrain dopamine system in relation to pain associated with sleep disturbances. Our study shows that chronic sleep deprivation decreases dopamine responses to noxious stimuli within the mouse nucleus accumbens, regulated by dopamine release and intracellular signals. Furthermore, we confirmed that the dopamine D₂ receptors play a critical role in the pain associated with chronic sleep deprivation. Importantly, we revealed that homer1a in D₂ receptor neurons enhances AMPA receptors expression.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1043-1054"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497475","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":"Exploring the Potential of Indole-3-acetic Acid Arylhydrazone Hybrids for Parkinson's Disease Treatment: A Comprehensive Evaluation of Neuroprotective, MAOB Inhibitory, and Antioxidant Properties.","authors":"Neda Anastassova, Magdalena Kondeva-Burdina, Nadya Hristova-Avakumova, Denitsa Stefanova, Miroslav Rangelov, Nadezhda Todorova, Denitsa Yancheva","doi":"10.1021/acschemneuro.4c00838","DOIUrl":"10.1021/acschemneuro.4c00838","url":null,"abstract":"<p><p>In the current study, a small series of five indole-3-acetic acid-derived arylhydrazone hybrids were synthesized and subjected to comprehensive evaluation of their neuropharmacological and radical-scavenging properties. Minimal neurotoxic effects were observed across diverse subcellular fractions, with particular emphasis on the compound <b>3a</b> bearing a 2,3-dihydroxy moiety, exhibiting superior neuroprotective effects against H₂O₂-induced oxidative stress by preserving the cell viability up to 68%. Noteworthy neuroprotection was observed in 6-OHDA-induced neurotoxicity using isolated rat brain synaptosomes, with compounds <b>3b</b> and <b>3c</b> displaying prominent effects. Compound <b>3a</b> demonstrated robust neuroprotective and antioxidant effects in models of <i>tert</i>-butyl hydroperoxide-induced oxidative stress on isolated rat brain mitochondria and nonenzyme-induced lipid peroxidation using isolated rat brain microsomes (Fe/AA). All compounds exhibited MAOB inhibition within the range of 0.130-0.493 μM, with compounds <b>3d</b>, <b>3e</b>, and <b>3a</b> showing notable selectivity against hMAOB. Molecular docking studies further validated ligand binding within MAOB active sites. The derivatives demonstrated scavenging activity and antioxidant effects against various ROS types, with compound <b>3a</b> consistently exhibiting the most potent activity. Structural modifications exerted discernible effects on scavenging capabilities and antioxidant effects, underscoring their potential therapeutic implications in neuroprotection and oxidative stress mitigation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1161-1181"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602957","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":"Decoding the Nectin Interactome: Implications for Brain Development, Plasticity, and Neurological Disorders.","authors":"Shreyash Santosh Yadav, Krishnamoorthy Srinivasan, Shyam Sunder Sharma, Ashok Kumar Datusalia","doi":"10.1021/acschemneuro.5c00069","DOIUrl":"10.1021/acschemneuro.5c00069","url":null,"abstract":"<p><p>The nectin family of cell adhesion molecules (CAMs) comprising nectins and nectin-like molecules has emerged as a key regulator of various pivotal neural processes, including neuronal development, migration, synapse formation, and plasticity. Nectins engage in homophilic and heterophilic interactions to mediate cell-cell adhesion, contributing to the establishment and maintenance of neural circuits. Their extracellular domains facilitate trans-synaptic interactions, while intracellular domains participate in signaling cascades influencing cytoskeletal dynamics and synaptic function. The exhibition of distinct localization patterns in neurons, astrocytes, and the blood-brain barrier underscores their diverse roles in the brain. The dysregulation of nectins has been implicated in several neurological disorders, such as neurodevelopmental disorders, depression, schizophrenia, and Alzheimer's disease. This review examines the structural and functional characteristics of nectins and their distribution and molecular mechanisms governing neural connectivity and cognition. It further discusses experimental studies unraveling nectin-mediated pathophysiology and potential therapeutic interventions targeting nectin-related pathways. Collectively, this comprehensive analysis highlights the significance of nectins in brain development, function, and disorders, paving the way for future research directions and clinical implications.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1000-1020"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536225","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":"Fluorescent Sensor for the Visualization of Amino Acid Neurotransmitters in Neurons Based on an S_NAr Reaction.","authors":"Ming Xu, Peeyush Yadav, Xin Liu, Kevin D Gillis, Timothy E Glass","doi":"10.1021/acschemneuro.5c00107","DOIUrl":"10.1021/acschemneuro.5c00107","url":null,"abstract":"<p><p>Glutamate is an important excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter. However, direct and accurate visualization of these important signaling agents by a chemical sensor is still very challenging. Here, a novel coumarin-based fluorescent sensor for the selective labeling and imaging of amino acids in neurons has been developed. This sensor system provides two binding sites for amino acids: an aldehyde group for the amine binding and a modified fluorobenzene for an unusual nucleophilic aromatic substitution (S_NAr) reaction of a carboxyl group. Spectroscopic studies reveal a large fluorescence enhancement upon reaction with glutamate. Compounds lacking both groups did not activate the sensor. A clear and efficient visualization of neurotransmitters in cultured hippocampus neurons was obtained by imaging studies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1238-1242"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595767","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":"Procognitive Potential of Neuroprotective Triazine 5-HT₆ Receptor Antagonists Tested on Chronic Activity In Vivo in Rats: Computer-Aided Insight into the Role of Chalcogen-Differences on the Pharmacological Profile.","authors":"Magdalena Jastrzębska-Więsek, Sabrina Garbo, Agnieszka Cios, Natalia Wilczyńska-Zawal, Anna Partyka, Ewelina Honkisz-Orzechowska, Ewa Żesławska, Jarosław Handzlik, Barbara Mordyl, Monika Głuch-Lutwin, Alessia Raucci, Marius Hittinger, Małgorzata Starek, Monika Dąbrowska, Wojciech Nitek, Tadeusz Karcz, Alicja Skórkowska, Joanna Gdula-Argasińska, Kinga Czarnota-Łydka, Patryk Pyka, Ewa Szymańska, Katarzyna Kucwaj-Brysz, Clemens Zwergel, Anna Wesołowska, Cecilia Battistelli, Jadwiga Handzlik","doi":"10.1021/acschemneuro.4c00873","DOIUrl":"10.1021/acschemneuro.4c00873","url":null,"abstract":"<p><p>Among serotonin receptors, the 5-HT₆ subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. This study aimed to extend the body of preclinical research on two naphthyl-derived methylpiperazine-1,3,5-triazine analogues with thioether (<b>WA-22</b>) or Se-ether (<b>PPK-32</b>) linkers, the newly described compounds having high affinity and selectivity for 5-HT₆ receptors and drug-like parameters in vitro. Thus, crystallography-supported deeper insight into their chemical properties, the comparison of their neuroprotective and pharmacokinetic profiles, and especially their impact on memory disturbances after chronic administration to rats were investigated. As a result, the chronic administration of <b>WA-22</b> completely reversed <b>(+)MK-801</b>-induced memory disturbances evaluated in the novel object recognition test (NORT) in rats. The pharmacokinetic and biochemical results support the notion that this 1,3,5-triazine 5-HT₆ receptor ligand could offer a promising therapeutic tool in CNS-related disorders. The selenium compound <b>PPK-32</b>, with a similar range of activity at acute administration, has shown even broader neuroprotective profiles, especially at the genetic level. However, for therapeutic use, its weaker pharmacokinetics (stability), which is a probable limit for action upon chronic administration, would require improvement, e.g., by an appropriate formulation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1190-1209"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527796","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}