A first in human sequential dose-escalation study investigating safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses of NS11821 in healthy male subjects - NS11821 First In Man Study

Start Date12 Aug 2009

Sponsor / Collaborator

Neurosearch

100 Clinical Results associated with GABRA2 x GABRA5 x GABRA3 x GABAA receptor

100 Translational Medicine associated with GABRA2 x GABRA5 x GABRA3 x GABAA receptor

0 Patents (Medical) associated with GABRA2 x GABRA5 x GABRA3 x GABAA receptor

Literatures (Medical) associated with GABRA2 x GABRA5 x GABRA3 x GABAA receptor

01 Jul 2024·Differentiation

Characterization of the zebrafish gabra1 germline loss of function allele confirms a function for Gabra1 in motility and nervous system development

Article

Author: Paz, David ; Estevao, Igor L ; Gil, Claudia B ; Gonzales, Annalise V ; Quintana, Anita M ; Castro, Victoria L ; Grajeda, Brian I ; Reyes-Nava, Nayeli G ; Pinales, Briana E ; Ellis, Cameron C ; Perez, Isaiah

Mutation of the GABRA1 gene is associated with neurodevelopmental defects and epilepsy. GABRA1 encodes for the α1 subunit of the γ-aminobutyric acid type A receptor (GABA_AR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have been developed to understand the function of GABRA1, but these models have produced complex and, at times, incongruent data. Thus, additional model systems are required to validate and substantiate previous results. We sought to provide initial phenotypic analysis of a novel germline mutant allele. Our analysis provides a solid foundation for the future use of this allele to characterize gabra1 functionally and pharmacologically using zebrafish. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafish gabra1 (sa43718 allele) gene. The sa43718 allele causes a decrease in gabra1 mRNA expression, which is associated with light induced hypermotility, one phenotype previously associated with seizure like behavior in zebrafish. Mutation of gabra1 was accompanied by decreased mRNA expression of gabra2, gabra3, and gabra5, indicating a reduction in the expression of additional α sub-units of the GABA_AR. Although multiple sub-units were decreased, larvae continued to respond to pentylenetetrazole (PTZ), indicating that a residual GABA_AR exists in the sa43718 allele. Proteomics analysis demonstrated that mutation of gabra1 is associated with abnormal expression of proteins that regulate synaptic vesicle fusion, vesicle transport, synapse development, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in the gabra1 gene result in seizure-like phenotypes with abnormal development of the GABA synapse. Our results add to the existing body of knowledge as to the function of GABRA1 during development and validate that zebrafish can be used to provide complete functional characterization of the gene.

27 Sep 2022·Evidence-Based Complementary and Alternative Medicine

Network Pharmacology-Based Exploration of the Mechanism of Action of Shugan Hewei Recipe in the Treatment of Gastroesophageal Reflux Disease with Anxiety and Depression

Article

Author: Wang, Hongwei ; Liu, Chunfang ; Xu, Tingting ; Zhang, Xiulian ; Geng, Lin ; Zhu, Shengliang ; Li, Li

The Shugan Hewei recipe (SHR) is a well-recognized traditional Chinese medicine (TCM) prescription that has been shown to significantly improve chest pain, acid regurgitation, and the mood of GERD. Nonetheless, the underlying mechanisms remain unclear. In this study, the active compounds and targets of SHR were predicted using network pharmacology. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were utilized to explore the therapeutic mechanism of SHR. Combined with the drug target obtained from network pharmacology, the therapeutic effect and mechanism of SHR were observed. SHR’s main active compounds included quercetin, kaempferol, and luteolin. The core targets of SHR and GERD were TGF-β1, IL-1β, IL-4, CXCL10, MAPK1, MAPK3, CXCL8, IL-10, IL-2, and FOS, involving virus infection, inflammatory response, and body immunity. The core targets of SHR during the treatment of mental disorders were GABRA1, GABRA2, GABRA3, GABRA5, and GABRA6, involving synaptic transmission and transmembrane movement. Animal experiments revealed that SHR could repair the lower esophageal mucosa, mediate inflammatory factors, and GABA receptors and improve the behavior of rats. Overall, our results substantiate that SHR has huge prospects for widespread application in treating GERD subjects with anxiety and depression.

01 Dec 2021·Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica

[Prediction of Q-markers of Citri Reticulatae Pericarpium volatile oil and GC-MS based quantitative analysis].

Article

Author: Yang, Ming ; Xiong, Yan-Fen ; Cai, Ke-Zhen ; Kang, Yong-Jie ; Li, Wen-Jing ; Wu, Meng-Qi ; Zhu, Li-Yun ; Liu, Xiao-Li ; Xiao, Shuai ; Zheng, Qin

This study was designed to predict the Q-markers of Citri Reticulatae Pericarpium volatile oil and conduct quantitative analysis by GC-MS. The common components of Citri Reticulatae Pericarpium volatile oil were detected by GC-MS. The network pharmacology approaches were utilized for constructing the component-target network and protein-protein interaction(PPI) network, followed by the GO and KEGG pathway enrichment analysis to clarify the pharmacological effects of common components. Molecular docking was conducted to observe the biological activities of common components, thus identifying the Q-markers of Citri Reticulatae Pericarpium volatile oil. The obtained Q-markers were subjected to quantitative analysis by GC-MS. The GC-MS analysis of 19 batches of Citri Reticulatae Pericarpium volatile oil revealed three common components, namely, D-limonene, γ-terpinene, and myrcene. The common components were analyzed based on network pharmacology, and the results showed that Citri Reticulatae Pericarpium volatile oil mainly acted on the core targets GABRA1, GABRA6, GABRA5, GABRA3, and GABRA2 through D-limonene and γ-terpinene, with five important pathways such as nicotine addiction and GABAergic synapse involved. The core targets were mainly distributed in olfactory region, cerebral cortex, cerebellum, basal ganglia, hippocampus, and amygdala to exert the pharmacological effects. As revealed by molecular docking, D-limonene and γ-terpinene exhibited good biological activities, so they were identified as the Q-markers of Citri Reticulatae Pericarpium volatile oil. The results of quantitative analysis showed that the volume fraction of D-limonene was within the range of 0.77-1.03 μL·mL~(-1), and that of γ-terpinene within the range of 0.04-0.13 μL·mL~(-1). The prediction of D-limonene and γ-terpinene as the Q-markers of Citri Reticulatae Pericarpium volatile oil has laid an experimental foundation for the establishment of the quality evaluation standard for Citri Reticulatae Pericarpium volatile oil.

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