Neuropharmacology最新文献_第9页

Intranasal LAG3 antibody infusion induces a rapid antidepressant effect via the hippocampal ERK1/2-BDNF signaling pathway in chronically stressed mice 鼻内注射 LAG3 抗体可通过海马 ERK1/2-BDNF 信号通路对慢性应激小鼠产生快速抗抑郁作用。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-15 DOI: 10.1016/j.neuropharm.2024.110118

Yunli Fang , Hainan Pan , Haojie Zhu , Hanxiao Wang , Minxiu Ye , Jie Ren , Jie Peng , Jinxin Li , Xu Lu , Chao Huang

{"title":"Intranasal LAG3 antibody infusion induces a rapid antidepressant effect via the hippocampal ERK1/2-BDNF signaling pathway in chronically stressed mice","authors":"Yunli Fang , Hainan Pan , Haojie Zhu , Hanxiao Wang , Minxiu Ye , Jie Ren , Jie Peng , Jinxin Li , Xu Lu , Chao Huang","doi":"10.1016/j.neuropharm.2024.110118","DOIUrl":"10.1016/j.neuropharm.2024.110118","url":null,"abstract":"<div><p>The decline of microglia in the dentate gyrus is a new phenomenon that may explain the pathogenesis of depression, and reversing this decline has an antidepressant effect. The development of strategies that restore the function of dentate gyrus microglia in under stressful conditions is becoming a new focus. Lymphocyte-activating gene-3 (LAG3) is an immune checkpoint expressed by immune cells including microglia. One of its functions is to suppress the expansion of immune cells. In a recent study, chronic systemic administration of a LAG3 antibody that readily penetrates the brain was reported to reverse chronic stress-induced hippocampal microglia decline and depression-like behaviors. We showed here that a single intranasal infusion of a LAG3 antibody (In-LAG3 Ab) reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in a dose-dependent manner, which was accompanied by an increase in brain-derived neurotrophic factor (BDNF) in the dentate gyrus. Infusion of an anti-BDNF antibody into the dentate gyrus, construction of knock-in mice with the BDNF Val68Met allele, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of In-LAG3 Ab. Activation of extracellular signal-regulated kinase1/2 (ERK1/2) is required for the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and BDNF decrease in the dentate gyrus. Moreover, both inhibition and depletion of microglia prevented the reversal effect of In-LAG3 Ab on CUS-induced depression-like behaviors and impairment of ERK1/2-BDNF signaling in the dentate gyrus. These results suggest that In-LAG3 Ab exhibits an antidepressant effect through microglia-mediated activation of ERK1/2 and synthesis of BDNF in the dentate gyrus.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"259 ","pages":"Article 110118"},"PeriodicalIF":4.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Neurolipidomics in schizophrenia: A not so well-oiled machine 精神分裂症的神经脂质组学：运转不灵的机器。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-15 DOI: 10.1016/j.neuropharm.2024.110117

Carlos Manuel Zapata-Martín del Campo , Garth L. Nicolson , Adonis Sfera

{"title":"Neurolipidomics in schizophrenia: A not so well-oiled machine","authors":"Carlos Manuel Zapata-Martín del Campo , Garth L. Nicolson , Adonis Sfera","doi":"10.1016/j.neuropharm.2024.110117","DOIUrl":"10.1016/j.neuropharm.2024.110117","url":null,"abstract":"<div><p>Most patients with schizophrenia (SCZ) do not exhibit violent behaviors and are more likely to be victims rather than perpetrators of violent acts. However, a subgroup of forensic detainees with SCZ exhibit tendencies to engage in criminal violations. Although numerous models have been proposed, ranging from substance use, serotonin transporter gene, and cognitive dysfunction, the molecular underpinnings of violence in SCZ patients remains elusive.</p><p>Lithium and clozapine have established anti-aggression properties and recent studies have linked low cholesterol levels and ultraviolet (UV) radiation with human aggression, while vitamin D3 reduces violent behaviors. A recent study found that vitamin D3, omega-3 fatty acids, magnesium, and zinc lower aggression in forensic population.</p><p>In this review article, we take a closer look at aryl hydrocarbon receptor (AhR) and the dysfunctional lipidome in neuronal membranes, with emphasis on cholesterol and vitamin D3 depletion, as sources of aggressive behavior. We also discuss modalities to increase the fluidity of neuronal double layer via membrane lipid replacement (MLR) and natural or synthetic compounds.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110117"},"PeriodicalIF":4.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Medial prefrontal cortex circuitry and social behaviour in autism 自闭症患者的内侧前额叶皮层回路和社交行为。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-14 DOI: 10.1016/j.neuropharm.2024.110101

Diego H. Mediane , Shinjini Basu , Emma N. Cahill , Paul G. Anastasiades

引用次数: 0

Influence of β2-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion β2-脱能选择性激动剂福莫特罗对伴有完全 VAChT 脱失的遗传性肌萎缩综合征猴子模型运动单元的影响。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-14 DOI: 10.1016/j.neuropharm.2024.110116

Leonardo Rossi , Bárbara I. Mota , Priscila A.C. Valadão , Matheus P.S. Magalhães-Gomes , Bruna S. Oliveira , Silvia Guatimosim , Luiz C.C. Navegantes , Aline S. Miranda , Marco A.M. Prado , Vânia F. Prado , Cristina Guatimosim

{"title":"Influence of β2-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion","authors":"Leonardo Rossi , Bárbara I. Mota , Priscila A.C. Valadão , Matheus P.S. Magalhães-Gomes , Bruna S. Oliveira , Silvia Guatimosim , Luiz C.C. Navegantes , Aline S. Miranda , Marco A.M. Prado , Vânia F. Prado , Cristina Guatimosim","doi":"10.1016/j.neuropharm.2024.110116","DOIUrl":"10.1016/j.neuropharm.2024.110116","url":null,"abstract":"<div><p>Congenital Myasthenic Syndromes (CMS) are a set of genetic diseases that affect the neuromuscular transmission causing muscular weakness. The standard pharmacological treatment aims at ameliorating the myasthenic symptom by acetylcholinesterase inhibitors. Most patients respond well in the short and medium term, however, over time the beneficial effects rapidly fade, and the efficacy of the treatment diminishes. Increasing evidence shows that β<sub>2</sub>-adrenergic agonists can be a suitable choice for the treatment of neuromuscular disorders, including CMS, as they promote beneficial effects in the neuromuscular system. The exact mechanism on which they rely is not completely understood, although patients and animal models respond well to the treatment, especially over extended periods. Here, we report the use of the long-lasting specific β<sub>2</sub>-adrenergic agonist formoterol in a myasthenic mouse model (mnVAChT-KD), featuring deletion of VAChT (Vesicular Acetylcholine Transporter) specifically in the α-motoneurons. Our findings demonstrate that formoterol treatment (300 μg/kg/day; sc) for 30 days increased the neuromuscular junction area, induced skeletal muscle hypertrophy and altered fibre type composition in myasthenic mice. Interestingly, β<sub>2</sub>-adrenergic agonists have shown efficacy even in the absence of ACh (acetylcholine). Our data provide important evidence supporting the potential of β<sub>2</sub>-adrenergic agonists in treating neuromuscular disorders of pre-synaptic origin and characterized by disruptions in nerve-muscle communication, through a direct and beneficial action within the motor unit.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110116"},"PeriodicalIF":4.6,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Enhanced interleukin-16-CD4 signaling in CD3 T cell mediates neuropathic pain via activating astrocytes in female mice CD3 T 细胞中白细胞介素-16-CD4 信号的增强通过激活雌性小鼠的星形胶质细胞介导神经性疼痛

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-11 DOI: 10.1016/j.neuropharm.2024.110115

Xuan Zhu , Xiang Li , Siyi Liu , Yun-Han Zhao , Xue-Ru Liu , Xing-Yu Liu , Rongrong Yao , Lixia Tian , Xin-Qi Liu , Fanjun Meng , Lingli Liang

{"title":"Enhanced interleukin-16-CD4 signaling in CD3 T cell mediates neuropathic pain via activating astrocytes in female mice","authors":"Xuan Zhu , Xiang Li , Siyi Liu , Yun-Han Zhao , Xue-Ru Liu , Xing-Yu Liu , Rongrong Yao , Lixia Tian , Xin-Qi Liu , Fanjun Meng , Lingli Liang","doi":"10.1016/j.neuropharm.2024.110115","DOIUrl":"10.1016/j.neuropharm.2024.110115","url":null,"abstract":"<div><p>Immune cells and interleukins play a crucial role in female-specific pain signaling. Interleukin 16 (IL-16) is a cytokine primarily associated with CD4<sup>+</sup> T cell function. While previous studies have demonstrated the important role of spinal CD4<sup>+</sup> T cells in neuropathic pain, the specific contribution of IL-16 to neuropathic pain remains unclear. In this study, by using a spinal nerve ligation (SNL)-induced neuropathic pain mice model, we found that SNL induced an increase in IL-16 mRNA levels, which persisted for a longer duration in female mice compared to male mice. Immunofluorescence analysis further confirmed enhanced IL-16- and CD4-positive signals in the spinal dorsal horn following SNL surgery in female mice. Knockdown of spinal IL-16 by siRNA or inhibition of CD4 by FGF22-IN-1, a CD4 inhibitor, attenuated established mechanical and thermal pain hypersensitivity induced by SNL. Furthermore, female mice injected with IL-16 intrathecally exhibited significant spontaneous pain, mechanical and thermal hyperalgesia, all of which could be alleviated by FGF22-IN-1 or a CD3 antibody. Additionally, IL-16 induced astrocyte activation but not microglial activation in the spinal dorsal horn of female mice. Meanwhile, astrocyte activation could be suppressed by the CD3 antibody. These results provide compelling evidence that IL-16 promotes astrocyte activation via CD4 on CD3<sup>+</sup> T cells, which is critical for maintaining neuropathic pain in female mice.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"259 ","pages":"Article 110115"},"PeriodicalIF":4.6,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141920030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Alcohol, flexible behavior, and the prefrontal cortex: Functional changes underlying impaired cognitive flexibility 酒精、灵活行为和前额叶皮层：认知灵活性受损背后的功能变化。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110114

Kathryn E. Nippert , Courtney P. Rowland , Elena M. Vazey , David E. Moorman

{"title":"Alcohol, flexible behavior, and the prefrontal cortex: Functional changes underlying impaired cognitive flexibility","authors":"Kathryn E. Nippert , Courtney P. Rowland , Elena M. Vazey , David E. Moorman","doi":"10.1016/j.neuropharm.2024.110114","DOIUrl":"10.1016/j.neuropharm.2024.110114","url":null,"abstract":"<div><p>Cognitive flexibility enables individuals to alter their behavior in response to changing environmental demands, facilitating optimal behavior in a dynamic world. The inability to do this, called behavioral inflexibility, is a pervasive behavioral phenotype in alcohol use disorder (AUD), driven by disruptions in cognitive flexibility. Research has repeatedly shown that behavioral inflexibility not only results from alcohol exposure across species but can itself be predictive of future drinking. Like many high-level executive functions, flexible behavior requires healthy functioning of the prefrontal cortex (PFC). The scope of this review addresses two primary themes: first, we outline tasks that have been used to investigate flexibility in the context of AUD or AUD models. We characterize these based on the task features and underlying cognitive processes that differentiate them from one another. We highlight the neural basis of flexibility measures, focusing on the PFC, and how acute or chronic alcohol in humans and non-human animal models impacts flexibility. Second, we consolidate findings on the molecular, physiological and functional changes in the PFC elicited by alcohol, that may contribute to cognitive flexibility deficits seen in AUD. Collectively, this approach identifies several key avenues for future research that will facilitate effective treatments to promote flexible behavior in the context of AUD, to reduce the risk of alcohol related harm, and to improve outcomes following AUD.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"260 ","pages":"Article 110114"},"PeriodicalIF":4.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner 长期富含饱和脂肪的饮食会以性别依赖的方式损害海马学习和记忆过程。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110108

Ana Belén Sanz-Martos , María Roca , Adrián Plaza , Beatriz Merino , Mariano Ruiz-Gayo , Nuria del Olmo

{"title":"Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner","authors":"Ana Belén Sanz-Martos , María Roca , Adrián Plaza , Beatriz Merino , Mariano Ruiz-Gayo , Nuria del Olmo","doi":"10.1016/j.neuropharm.2024.110108","DOIUrl":"10.1016/j.neuropharm.2024.110108","url":null,"abstract":"<div><p>Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates <em>Gria1</em> expression specifically in males. In females, SOLF downregulates the gene expression of <em>Gria1/2</em><em>/3</em> and <em>Grin1/2A/2B</em> glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"259 ","pages":"Article 110108"},"PeriodicalIF":4.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0028390824002776/pdfft?md5=fd90a8a750a1c5460c4f9705e5580c6c&pid=1-s2.0-S0028390824002776-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway Deguelin 通过抑制 CCL2/NFκB 信号通路抑制胶质母细胞瘤的进展。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110109

Yiming Qian , Jianhong Dong , Wei Zhang , Xiumin Xue , Zhenrong Xiong , Weiquan Zeng , Qian Wang , Ziwei Fan , Zhenxing Zuo , Zhihui Huang , Yuanyuan Jiang

{"title":"Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway","authors":"Yiming Qian , Jianhong Dong , Wei Zhang , Xiumin Xue , Zhenrong Xiong , Weiquan Zeng , Qian Wang , Ziwei Fan , Zhenxing Zuo , Zhihui Huang , Yuanyuan Jiang","doi":"10.1016/j.neuropharm.2024.110109","DOIUrl":"10.1016/j.neuropharm.2024.110109","url":null,"abstract":"<div><p>Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae <em>Mundulea sericea</em> (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that <em>CCL2</em> (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB <em>in vivo</em>. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"259 ","pages":"Article 110109"},"PeriodicalIF":4.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF MSK1是经验和安巴碱依赖性增强空间参照记忆和逆转学习的必要条件。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110110

Lorenzo Morè , Lucia Privitera , Marcia Lopes , J. Simon C. Arthur , Julie C. Lauterborn , Sonia A.L. Corrêa , Bruno G. Frenguelli

{"title":"MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF","authors":"Lorenzo Morè , Lucia Privitera , Marcia Lopes , J. Simon C. Arthur , Julie C. Lauterborn , Sonia A.L. Corrêa , Bruno G. Frenguelli","doi":"10.1016/j.neuropharm.2024.110110","DOIUrl":"10.1016/j.neuropharm.2024.110110","url":null,"abstract":"<div><div>There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"261 ","pages":"Article 110110"},"PeriodicalIF":4.6,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors Zelquistinel 作用于细胞外结合域，调节 N-甲基-D-天冬氨酸受体的细胞内钙失活。

IF 4.6 2区医学

Neuropharmacology Pub Date : 2024-08-06 DOI: 10.1016/j.neuropharm.2024.110100

Xiao-lei Zhang , Yong-Xin Li , Nils Berglund , Jeffrey S. Burgdorf , John E. Donello , Joseph R. Moskal , Patric K. Stanton

{"title":"Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors","authors":"Xiao-lei Zhang , Yong-Xin Li , Nils Berglund , Jeffrey S. Burgdorf , John E. Donello , Joseph R. Moskal , Patric K. Stanton","doi":"10.1016/j.neuropharm.2024.110100","DOIUrl":"10.1016/j.neuropharm.2024.110100","url":null,"abstract":"<div><p>Stinels are a novel class of N-methyl-<span>d</span>-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca<sup>2+</sup> intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca<sup>2+</sup>-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.</p></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"259 ","pages":"Article 110100"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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