更新于：2024-11-01

GluN1 x NLRP3

更新于：2024-11-01

基本信息

关联

项与 GluN1 x NLRP3 相关的药物

YA-101

靶点

GluN1 x NLRP3

作用机制

GluN1抑制剂 [+1]

在研机构

Yoda Pharmaceuticals, Inc.初创企业

原研机构

Yoda Pharmaceuticals, Inc.初创企业

在研适应症

多系统萎缩 [+2]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 GluN1 x NLRP3 相关的临床试验

ACTRN12623001117606 / Recruiting临床1期

A Double-Blind, Placebo-Controlled, Single Dose and Multiple Ascending Dose, Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetics of YA-101 in Healthy Subjects

开始日期2023-10-12

申办/合作机构-

100 项与 GluN1 x NLRP3 相关的临床结果

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100 项与 GluN1 x NLRP3 相关的转化医学

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0 项与 GluN1 x NLRP3 相关的专利（医药）

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项与 GluN1 x NLRP3 相关的文献（医药）

2021-12-01·Journal of Neuroinflammation1区 · 医学

HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury

1区 · 医学

ArticleOA

作者: Zhou, Yuan-Guo ; Liu, Dong ; Zhao, Yan ; Li, Ping ; Huang, Zhi-Zhong ; Ning, Ya-Lei ; Tan, Si-Wei ; Yang, Nan

AbstractBackgroundCognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4–8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear.MethodsMice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI. Levels of NLRP3 inflammasome and inflammatory factors such as IL-1β and HMGB1 were detected in post-injury hippocampal tissue, as well as long-term potentiation. Behaviors were assessed by T-maze test, novel object recognition, and nesting tests. Glycyrrhizin was used to antagonize HMGB1. Calcium imaging were performed on primary neuronal cultures.ResultsBy using the NLRP3-knockout TBI model, we found that the continuous activation of the NLRP3 inflammasome and high mobility group box 1 (HMGB1) release were closely related to cognitive impairment. We also found that inhibition of HMGB1 improved LTP reduction and cognitive function by increasing the phosphorylation level of the NMDAR1 subunit at serine 896 while reducing NLRP3 inflammasome activation.ConclusionNLRP3 inflammasome damages memory in the late stage of TBI primarily through HMGB1 upregulation and provides an explanation for the long-term progression of cognitive dysfunction.

2015-10-01·Chinese Journal of Traumatology4区 · 医学

N-methyl-D-aspartic acid receptor 1 (NMDAR1) aggravates secondary inflammatory damage induced by hemin-NLRP3 pathway after intracerebral hemorrhage

4区 · 医学

Article

作者: Xiao-Feng Wu ; Xun Weng ; Qing Ouyang ; Rui Liu ; Yue Tian ; Xiang Chu ; Lei Li ; Lin Li ; Feng Guo ; Yan Tan

OBJECTIVEInflammation plays a critical role in secondary brain damage after intracerebral hemorrhage (ICH). However, the mechanisms of inflammatory injury following ICH are still unclear, particularly the involvement of NLRP3 inflammasome, which are crucial to sterile inflammatory responses. In this study, we aim to test the hypothesis that NLRP3 signaling pathway takes a vital position in ICH-induced secondary inflammatory damage and detect the role of N-methyl-D-aspartic acid receptor 1 (NMDAR1) in this progress.METHODSICH was induced in mice by microinjection of hemin into the striatum. The protein levels of NMDAR1, NMDAR1 phosphorylation, NLRP3 and IL-1b were measured by Western blot. The binding of NMDAR1 to NLRP3 was detected by immunoprecipitation.RESULTSThe expression of NMDAR1, NMDAR1 phosphorylation, NLRP3 and IL-1b were rapidly increased after ICH. Hemin treatment enhanced NMDAR1 expression and NMDAR1 phosphorylation, as well in cultured microglial cells treated by hemin. Hemin up regulated NLRP3 and IL-1b level, which was reversed by MK801 (NMDAR antagonist) in vitro. Hemin also promoted the binding of NMDAR1 to NLRP3.CONCLUSIONOur findings suggest that NMDAR1 plays a pivotal role in hemin-induced NLRP3-mediated inflammatory damage through synergistic activation.

Scientific Reports3区 · 综合性期刊

An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes

3区 · 综合性期刊

ArticleOA

作者: Liu, Wei ; Huang, Yan-Hong ; Chen, Chen ; Han, Jian-Zhong ; Zhou, Zhi-Guang ; Peng, Xiang-Ping ; Guo, Jia ; Zhao, Fei-Yan ; Feng, Dan-Dan ; Luo, Zi-Qiang ; Li, Chen ; Yue, Shao-Jie ; Yang-Li ; Cheng, Qing-Mei ; Huang, Xiao-Ting

AbstractIn the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucoseviaactivation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of β-cells under chronic high-glucose exposure. Long-term treatment of β-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated byGluN1knockout. The NMDAR antagonist MK-801 orGluN1knockout prevented high-glucose-induced dysfunction in β-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in β-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by hyperglycemia.