ACS Chemical Neuroscience最新文献

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A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules 评估结构和表型相关神经活性分子的多模式体内方法
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-17 DOI: 10.1021/acschemneuro.4c00426
Matthew N. McCarroll, Elizabeth Sisko, Jung Ho Gong, Jinfeng Teng, Jack Taylor, Douglas Myers-Turnbull, Drew Young, Grant Burley, Lain X. Pierce, Ryan E. Hibbs, David Kokel, Jason K. Sello
{"title":"A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules","authors":"Matthew N. McCarroll, Elizabeth Sisko, Jung Ho Gong, Jinfeng Teng, Jack Taylor, Douglas Myers-Turnbull, Drew Young, Grant Burley, Lain X. Pierce, Ryan E. Hibbs, David Kokel, Jason K. Sello","doi":"10.1021/acschemneuro.4c00426","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00426","url":null,"abstract":"A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABA<sub>A</sub> potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABA<sub>A</sub> receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules’ nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251283","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 Evaluation of 18F-Labeled Phenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron Emission Tomography Imaging 用于正电子发射断层成像的 18F 标记苯基哌嗪样多巴胺 D3 受体放射性配体的合成与评估
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-14 DOI: 10.1021/acschemneuro.4c00177
Ge Zhang, Shilun Zhao, Zuoquan Zhao, Chenhao Jia, Yuxuan Zhang, Jingquan Xue, Yu Liu, Wenjiang Yang
{"title":"Synthesis and Evaluation of 18F-Labeled Phenylpiperazine-like Dopamine D3 Receptor Radioligands for Positron Emission Tomography Imaging","authors":"Ge Zhang, Shilun Zhao, Zuoquan Zhao, Chenhao Jia, Yuxuan Zhang, Jingquan Xue, Yu Liu, Wenjiang Yang","doi":"10.1021/acschemneuro.4c00177","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00177","url":null,"abstract":"The dopamine D3 receptor (D3R) is important in the pathophysiology of various neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, drug addiction, and Parkinson’s disease. Positron emission tomography (PET) with innovative radioligands provides an opportunity to assess D3R in vivo and to elucidate D3R-related disease mechanisms. Herein, we present the synthesis of eight <sup>18</sup>F-labeled phenylpiperazine-like D3R-selective radioligands possessing good radiochemical purity (&gt;97%), in vitro stability (&gt;95%), and befitting lipophilicity. Based on in vitro binding assays and static microPET studies, the phenylpiperazine-like radioligands [<sup>18</sup>F]FBPC01 and [<sup>18</sup>F]FBPC03 were chosen as lead radioligands targeting D3R. Molecular docking further elucidated their binding mechanism. Radiolabeling conditions were optimized and then applied to an automated radiolabeling process, affording products with high specific activity (&gt;112 GBq/μmol). Dynamic rat PET study demonstrated the specific binding of [<sup>18</sup>F]FBPC01 and [<sup>18</sup>F]FBPC03 to D3R in the brain ventricles and the pituitary gland. Validated by dynamic PET data analysis, biodistribution study, and metabolism analysis, [<sup>18</sup>F]FBPC03 exhibited the highest PET signal-to-noise ratio, good D3R-specific binding in the brain ventricles and pituitary gland of rats with few off-target binding, negligible defluorination, and stable brain metabolism, which indicated that [<sup>18</sup>F]FBPC03 was a promising D3R radioligand.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251285","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
Automated, Transferable, and Ethanol-Free Radiosynthesis of [11C]Butanol 自动化、可转移、无乙醇的[11C]丁醇放射合成技术
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-13 DOI: 10.1021/acschemneuro.4c00455
Olujide Oyeniran, Linshan Liu, Confidence Raymond, Paulien Moyaert, Michael S. Kovacs, Udunna C. Anazodo, Justin W. Hicks
{"title":"Automated, Transferable, and Ethanol-Free Radiosynthesis of [11C]Butanol","authors":"Olujide Oyeniran, Linshan Liu, Confidence Raymond, Paulien Moyaert, Michael S. Kovacs, Udunna C. Anazodo, Justin W. Hicks","doi":"10.1021/acschemneuro.4c00455","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00455","url":null,"abstract":"Cerebral blood flow and blood–brain barrier permeability assessment are crucial hemodynamic parameters to measure under neurological conditions. In conjunction with positron emission tomography (PET), oxygen-15-labeled water has emerged as a gold standard for measuring cerebral perfusion; however, at higher flow rates, [<sup>15</sup>O]water extraction becomes nonlinear. In such a scenario, freely diffusible [<sup>11</sup>C]butanol can provide a truer estimate. Radiosyntheses of [<sup>11</sup>C]butanol reported to date are protracted, are not automated, or require ethanol in the final formulation. By using a flow-based, captive solvent approach on a commercially available radiosynthesizer, we automated and reduced the synthesis time to 28 min. Forgoing cartridge-based purification for an aqueous high-performance liquid chromatography method, we obtained high purity [<sup>11</sup>C]butanol in ethanol-free phosphate buffered saline in sufficient yields for clinical PET studies. We here report our expedited, automated, and ethanol-free radiosynthesis of [<sup>11</sup>C]butanol along with preliminary imaging of a porcine subject.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196602","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
Saroglitazar Enhances Memory Functions and Adult Neurogenesis via Up-Regulation of Wnt/β Catenin Signaling in the Rat Model of Dementia Saroglitazar 通过上调 Wnt/β Catenin 信号增强大鼠痴呆模型的记忆功能和成神经元形成
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-12 DOI: 10.1021/acschemneuro.4c00167
Sandeep Kumar Mishra, Vaibhav Mishra
{"title":"Saroglitazar Enhances Memory Functions and Adult Neurogenesis via Up-Regulation of Wnt/β Catenin Signaling in the Rat Model of Dementia","authors":"Sandeep Kumar Mishra, Vaibhav Mishra","doi":"10.1021/acschemneuro.4c00167","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00167","url":null,"abstract":"Peroxisome proliferator-activated receptors (PPARs) have emerged as a promising target for the treatment of various neurodegenerative disorders. Studies have shown that both PPAR α &amp; γ individually modulate various pathophysiological events like neuroinflammation and insulin resistance, which are known to variedly affect neurogenesis. Our study aimed to evaluate the effect of saroglitazar (SGZR), a dual PPAR agonist, on adult neurogenesis and spatial learning and memory, in intracerebroventricular streptozotocin (ICV STZ)-induced dementia in rats. We have found that SGZR at the dose of 4 mg/kg per oral showed significant improvement in learning and memory compared to ICV STZ-treated rats. A substantial increase in neurogenesis was observed in the subventricular zone (SVZ) and the dentate gyrus (DG), as indicated by an increase in the number of 5-bromo-2′-deoxyuridine (BrdU)<sup>+</sup> cells, BrdU<sup>+</sup> nestin<sup>+</sup> cells, and doublecortin (DCX)<sup>+</sup>cells. Treatment with SGZR also decreased the active form of glycogen synthase kinase 3β (GSK3β) and hence enhanced the nuclear translocation of the β-catenin. Enhanced expression of Wnt transcription factors and target genes indicates that the up-regulation of Wnt signaling might be involved in the observed increase in neurogenesis. Hence, it can be concluded that the SGZR enhances memory functions and adult neurogenesis via the upregulation of Wnt β-catenin signaling in ICV STZ-treated rats.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196603","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
Bifunctional Inhibitor Lentinan Inhibits Fibrillogenesis of Amyloid-β Protein and α-Synuclein and Alleviates Their Cytotoxicity: In Vitro and In Vivo Studies 双功能抑制剂 Lentinan 可抑制淀粉样β蛋白和α-突触核蛋白的纤丝化并减轻其细胞毒性:体外和体内研究
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-12 DOI: 10.1021/acschemneuro.4c00164
Wen Gao, Qinchen Dong, Xinni Wu, Yang Wang, Jinbi Li, Qingfu Zhang, Fuping Lu, Fufeng Liu
{"title":"Bifunctional Inhibitor Lentinan Inhibits Fibrillogenesis of Amyloid-β Protein and α-Synuclein and Alleviates Their Cytotoxicity: In Vitro and In Vivo Studies","authors":"Wen Gao, Qinchen Dong, Xinni Wu, Yang Wang, Jinbi Li, Qingfu Zhang, Fuping Lu, Fufeng Liu","doi":"10.1021/acschemneuro.4c00164","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00164","url":null,"abstract":"Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in the world. Misfolding of β-amyloid (Aβ) and α-synuclein (α-syn) and subsequent fibril formation are closely associated with the pathogenesis of AD and PD, respectively. Lentinan is a natural product commonly used in medicine and dietary supplements. It has potential antitumor, anti-inflammatory, and antiviral effects, but the underlying mechanism of its action on AD and PD remains unclear. In this study, lentinan inhibited the formation of Aβ and α-syn fibers in a dose-dependent manner and disrupted their mature fibers. Lentinan inhibited the conversion of Aβ and α-syn conformations to β-sheet-rich conformations. Additionally, lentinan protected <i>Caenorhabditis elegans</i> against damage caused by the accumulation of Aβ and α-syn aggregation and prolonged their lifespan. Notably, the beneficial effects of lentinan in AD and PD mice were also demonstrated, including ameliorating the cognitive and memory impairments in AD mice and behavioral deficits in PD mice. Finally, molecular interactions between lentinan and Aβ/α-syn pentamers were also explored using molecular docking.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196627","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
The Antiproteinopathy, Antioxidant, and Antiapoptotic Effects of Methylene Blue and 4-Phenylbutyric Acid Alone, and in Combination on Familial Alzheimer’s Disease PSEN1 I416T Cholinergic-Like Neurons 亚甲基蓝和 4-苯基丁酸单独或联合使用对家族性阿尔茨海默病 PSEN1 I416T 胆碱能样神经元的抗蛋白病、抗氧化和抗凋亡作用
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-11 DOI: 10.1021/acschemneuro.4c00472
Nicolas Gomez-Sequeda, Marlene Jimenez-Del-Rio, Carlos Velez-Pardo
{"title":"The Antiproteinopathy, Antioxidant, and Antiapoptotic Effects of Methylene Blue and 4-Phenylbutyric Acid Alone, and in Combination on Familial Alzheimer’s Disease PSEN1 I416T Cholinergic-Like Neurons","authors":"Nicolas Gomez-Sequeda, Marlene Jimenez-Del-Rio, Carlos Velez-Pardo","doi":"10.1021/acschemneuro.4c00472","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00472","url":null,"abstract":"Familial Alzheimer’s disease (FAD) is a chronic neurological condition that progresses over time. Currently, lacking a viable treatment, the use of multitarget medication combinations has generated interest as a potential FAD therapy approach. In this study, we examined the effects of 4-phenylbutyric acid (4-PBA) and methylene blue (MB) either separately or in combination on PSEN1 I416T cholinergic-like neuron cells (ChLNs), which serve as a model for FAD. We found that MB was significantly efficient at reducing the accumulation of intracellular Aβ, phosphorylation of TAU Ser202/Thr205, and increasing Δψm, whereas 4-PBA was significantly efficient at diminishing oxidation of DJ-1Cys106-SH, expression of TP53, and increasing ACh-induced Ca<sup>2+</sup> influx. Both agents were equally effective at blunting phosphorylated c-JUN at Ser63/Ser73 and activating caspase 3 (CASP3) into cleaved caspase 3 (CC3) on mutant cells. Combination of MB and 4-PBA at middle (0.1, 1) concentration significantly reduced iAβ, p-TAU, and oxDJ-1 and augmented the ACh-induced Ca<sup>2+</sup> influx compared to combined agents at low (0.05, 0.5) or high (0.5, 5) concentration. However, combined MB and 4-PBA were efficient only at dropping DJ-1Cys106-SO3 and increasing ACh-induced Ca<sup>2+</sup> inward in mutant ChLNs. Our data show that the reagents MB and 4-PBA alone possess more than one action (e.g., antiamyloid, antioxidant, anti-TAU, antiapoptotic, and ACh-induced Ca<sup>2+</sup> influx enhancers), that in combination might cancel or diminish each other. Together, these results strongly argue that MB and 4-PBA might protect PSEN1 I416T ChLNs from Aβ-induced toxicity by working intracellularly as anti-Aβ and anti-Tau agents, improving Δψm and cell survival, and extracellularly, by increasing ACh-induced Ca<sup>2+</sup> ion influx. MB and 4-PBA are promising drugs with potential for repurposing in familial AD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196605","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
Classics in Chemical Neuroscience: Muscimol 化学神经科学经典:麝香草酚
IF 5 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-10 DOI: 10.1021/acschemneuro.4c00304
Diego Rivera-Illanes, Gonzalo Recabarren-Gajardo
{"title":"Classics in Chemical Neuroscience: Muscimol","authors":"Diego Rivera-Illanes, Gonzalo Recabarren-Gajardo","doi":"10.1021/acschemneuro.4c00304","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00304","url":null,"abstract":"Muscimol (<b>3</b>) is a psychoactive isoxazole present in various <i>Amanita</i> mushrooms, along with ibotenic acid and muscarine. It is structurally related to GABA and acts as a GABA<sub>A</sub> agonist with great affinity. Muscimol use dates back to Siberian shamanic cultures as an entheogen, where it was ingested orally to exert psychoactive effects. Although not approved for clinical use, its potential and use as a research tool in neuroscience is of immense value, with <sup>3</sup>H-muscimol being used as a radioligand in GABA receptor research. Since its discovery in the early 60s, many research groups have worked on the synthesis of the compound. Recent research suggests the potential use of muscimol in neuropathic pain relief and other potential uses are also being studied. In this review, we will cover the history, chemistry, pharmacology and overall importance of the compound.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196604","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
Classics in Chemical Neuroscience: Muscimol 化学神经科学经典:麝香草酚
IF 4.1 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-10 DOI: 10.1021/acschemneuro.4c0030410.1021/acschemneuro.4c00304
Diego Rivera-Illanes,  and , Gonzalo Recabarren-Gajardo*, 
{"title":"Classics in Chemical Neuroscience: Muscimol","authors":"Diego Rivera-Illanes,&nbsp; and ,&nbsp;Gonzalo Recabarren-Gajardo*,&nbsp;","doi":"10.1021/acschemneuro.4c0030410.1021/acschemneuro.4c00304","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00304https://doi.org/10.1021/acschemneuro.4c00304","url":null,"abstract":"<p >Muscimol (<b>3</b>) is a psychoactive isoxazole present in various <i>Amanita</i> mushrooms, along with ibotenic acid and muscarine. It is structurally related to GABA and acts as a GABA<sub>A</sub> agonist with great affinity. Muscimol use dates back to Siberian shamanic cultures as an entheogen, where it was ingested orally to exert psychoactive effects. Although not approved for clinical use, its potential and use as a research tool in neuroscience is of immense value, with <sup>3</sup>H-muscimol being used as a radioligand in GABA receptor research. Since its discovery in the early 60s, many research groups have worked on the synthesis of the compound. Recent research suggests the potential use of muscimol in neuropathic pain relief and other potential uses are also being studied. In this review, we will cover the history, chemistry, pharmacology and overall importance of the compound.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237486","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
Reversible Control of Native GluN2B-Containing NMDA Receptors with Visible Light 用可见光可逆地控制原生含 GluN2B 的 NMDA 受体
IF 4.1 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-06 DOI: 10.1021/acschemneuro.4c0024710.1021/acschemneuro.4c00247
Chloé Geoffroy, Romain Berraud-Pache, Nicolas Chéron, Isabelle McCort-Tranchepain, Julia Doria, Pierre Paoletti and Laetitia Mony*, 
{"title":"Reversible Control of Native GluN2B-Containing NMDA Receptors with Visible Light","authors":"Chloé Geoffroy,&nbsp;Romain Berraud-Pache,&nbsp;Nicolas Chéron,&nbsp;Isabelle McCort-Tranchepain,&nbsp;Julia Doria,&nbsp;Pierre Paoletti and Laetitia Mony*,&nbsp;","doi":"10.1021/acschemneuro.4c0024710.1021/acschemneuro.4c00247","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00247https://doi.org/10.1021/acschemneuro.4c00247","url":null,"abstract":"<p >NMDA receptors (NMDARs) are glutamate-gated ion channels playing a central role in synaptic transmission and plasticity. NMDAR dysregulation is linked to various neuropsychiatric disorders. This is particularly true for GluN2B-containing NMDARs (GluN2B-NMDARs), which have major pro-cognitive, but also pro-excitotoxic roles, although their exact involvement in these processes remains debated. Traditional GluN2B-selective antagonists suffer from slow and irreversible effects, limiting their use in native tissues. We therefore developed OptoNAM-3, a photoswitchable negative allosteric modulator selective for GluN2B-NMDARs. OptoNAM-3 provided light-induced reversible inhibition of GluN2B-NMDAR activity with precise temporal control both in vitro and in vivo on the behavior of freely moving <i>Xenopus</i> tadpoles. When bound to GluN2B-NMDARs, OptoNAM-3 displayed remarkable red-shifting of its photoswitching properties allowing the use of blue light instead of UV light to turn-off its activity, which we attributed to geometric constraints imposed by the binding site onto the azobenzene moiety of the ligand. This study therefore highlights the importance of the binding site in shaping the photochemical properties of azobenzene-based photoswitches. In addition, by enabling selective, fast, and reversible photocontrol of native GluN2B-NMDARs with in vivo compatible photochemical properties (visible light), OptoNAM-3 should be a useful tool for the investigation of the GluN2B-NMDAR physiology in native tissues.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237442","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
Kinetic Properties of Glutamate Carboxypeptidase II Partially Purified from Leukodystrophy Patient’s Serum 从白质营养不良症患者血清中部分纯化的谷氨酸羧肽酶 II 的动力学特性
IF 4.1 3区 医学
ACS Chemical Neuroscience Pub Date : 2024-09-06 DOI: 10.1021/acschemneuro.4c0036610.1021/acschemneuro.4c00366
Aws Z. Abdulmajeed*,  and , Wasan Nazhan, 
{"title":"Kinetic Properties of Glutamate Carboxypeptidase II Partially Purified from Leukodystrophy Patient’s Serum","authors":"Aws Z. Abdulmajeed*,&nbsp; and ,&nbsp;Wasan Nazhan,&nbsp;","doi":"10.1021/acschemneuro.4c0036610.1021/acschemneuro.4c00366","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00366https://doi.org/10.1021/acschemneuro.4c00366","url":null,"abstract":"<p >Glutamate carboxypeptidase II (GCPII), a metallopeptidase, is a recently identified pharmacologically targeted protein that is predominantly expressed in the human central nervous system, where it degrades the most abundant neuropeptide in the brain, <i>N</i>-acetyl aspartate glutamate, releasing free glutamate. Dysregulated glutamate release is associated with numerous neurological disorders and brain inflammation. The present study was designed to evaluate the activity of GCPII in 60 serum samples from patients with leukodystrophy and 30 samples from a control group with an age of less than 10 years. Subsequently, the enzyme was purified from the serum of leukodystrophy patients for experimental studies using ion exchange and gel filtration techniques to enhance the enzyme purity and reduce impurities. Finally, the kinetic properties of the purified enzyme were measured. The results of the present study demonstrated a reduction in the efficacy of the enzyme in comparison to the control group at a significance level of <i>P</i> ≤ 0.00003. Additionally, the kinetic study of the purified enzyme revealed a Michaelis–Menten constant value of 0.012 μM and a maximum velocity of 1.1318 μmol min<sup>–1</sup>. As demonstrated by the Lineweaver–Burk plot, using folate as the substrate, the <i>K</i><sub>m</sub> value indicates the high affinity of the enzyme for folate, which is a crucial consideration in the development of therapies for neurological diseases. Additionally, the enzyme exhibited optimal activity at 37 °C and pH 7.4, with an incubation time of 5 min. The significance of GCPII in patients with leukodystrophy is 2-fold: first, it may serve as an early diagnostic marker for leukodystrophy, and second, it could represent a potential therapeutic target for neurological disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237448","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
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