The purpose of this study is to test whether a new treatment will be safe and effective in treating pain. Patients with diabetic peripheral neuropathy will be included.

开始日期2008-11-01

申办/合作机构

Eli Lilly & Co.

NCT00790790 / Completed临床2期

A Phase 2 Study of the Effects of LY545694, an iGluR5 Antagonist, in the Treatment of Subjects With Osteoarthritis Knee Pain

To gather data on whether a new drug for osteoarthritis knee pain will be safe and have an effect on pain levels.

开始日期2008-11-01

申办/合作机构

Eli Lilly & Co.

NCT00832546 / Completed临床1期

A Double-Blind, Randomized, Placebo Controlled, Cross-Over, Safety Tolerance and Experimental Hyperalgesia Study of Oral NGX426 in Healthy Male Volunteers

The purpose of this study is to determine the effects of NGX426 on intradermal capsaicin induced pain in hyperalgesia.

开始日期2008-05-01

申办/合作机构

TorreyPines Therapeutics, Inc.

100 项与 AMPA receptor x GluR-5 相关的临床结果

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100 项与 AMPA receptor x GluR-5 相关的转化医学

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0 项与 AMPA receptor x GluR-5 相关的专利（医药）

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项与 AMPA receptor x GluR-5 相关的文献（医药）

2024-01-01·Oncology Research

GRIK1 promotes glioblastoma malignancy and is a novel prognostic factor of poor prognosis

Article

作者: Hou, Guoqiang ; Hu, Weixing ; Xu, Xinhang

Primary tumors of the central nervous system (CNS) are classified into over 100 different histological types. The most common type of glioma is derived from astrocytes, and the most invasive glioblastoma (WHO IV) accounts for over 57% of these tumors. Glioblastoma (GBM) is the most common and fatal tumor of the CNS, with strong growth and invasion capabilities, which makes complete surgical resection almost impossible. Despite various treatment methods such as surgery, radiotherapy, and chemotherapy, glioma is still an incurable disease, and the median survival time of patients with GBM is shorter than 15 months. Thus, molecular mechanisms of GBM characteristic invasive growth need to be clarified to improve the poor prognosis. Glutamate ionotropic receptor kainate type subunit 1 (GRIK1) is essential for brain function and is involved in many mental and neurological diseases. However, GRIK1's pathogenic roles and mechanisms in GBM are still unknown. Single-nuclear RNA sequencing of primary and recurrent GBM samples revealed that GRIK1 expression was noticeably higher in the recurrent samples. Moreover, immunohistochemical staining of an array of GBM samples showed that high levels of GRIK1 correlated with poor prognosis of GBM, consistent with The Cancer Genome Atlas database. Knockdown of GRIK1 retarded GBM cells growth, migration, and invasion. Taken together, these findings show that GRIK1 is a unique and important component in the development of GBM and may be considered as a biomarker for the diagnosis and therapy in individuals with GBM.

2023-09-01·Combinatorial Chemistry & High Throughput Screening

Research on the Material Basis and Mechanism of Kudzu Root in Preventing and Treating Cerebral Ischemia based on Network Pharmacology

Article

作者: Wang, Song ; Zhu, Weifeng ; Xu, Ziwei ; Li, Bingtao ; Wang, Shuaikang ; Wang, Jingjing ; Xie, Yongyan ; Lu, Longhui ; Yao, Wei ; Yan, Feixia ; Zhu, Xudong ; Liu, Ronghua ; Zhu, Na ; Huang, Liping ; Qiu, Xiaopeng

Background:It has been shown that Kudzu root has significant pharmacological effects such as improving microcirculation, dilating coronary arteries, and increasing cerebral and coronary blood flow, but its material basis and mechanism of action are not clear.Objective:The aim of this study was to investigate the mechanism of action of Kudzu root in the prevention and treatment of cerebral ischemia (CI) through network pharmacology combined with animal experiments.Methods:The components of kudzu root were screened by using the Chemistry Database, Chinese Academy of Science. Linpinski's five rules were used to perform pharmacophore-like analysis to obtain the active ingredients of Kudzu root. The Swiss Target Prediction Service database was used to predict the potential protein targets of kudzu root components associated with CI. An active ingredient-target network was constructed by using Cytoscape 3.6.0. A rat model of middle cerebral artery occlusion (MCAO) was established, then the main targets and signaling pathways predicted were verified by observing the area of cerebral infarction and Western blot experiments.Results:In total, 84 major active compounds and 34 targets included gerberoside, belonging to the isoflavone class, gallic acid, amino acid class, 4-Methylphenol, phenolic class, and quercetin, and flavonoid class (Flavonoids). The targets covered were proteins related to excitatory amino acids and calcium overload, including Excitatory amino acid transporter 2 (SLC1A2), Glutamate receptor ionotropic, kainate 1 (GRIK1), Glutamate receptor ionotropic, NMDA 1 (GRIN1), Glutamate receptor 2(GRIA2), Calcium/calmodulin-dependent protein kinase II (CaMKII), Neuronal nitric oxide synthase(nNOS). Glutamatergic energy is prominent, and calcium transport across the membrane is central to the network and occupies an important position.Conclusion:Kudzu root can significantly reduce neurological damage in rats with CI, and also significantly reduce the rate of cerebral infarction. It is worth noting that kudzu root can prevent and treat CI by reducing excitatory amino acid toxicity and improving calcium overload.

2022-07-13·The Journal of Neuroscience

The Antiseizure Drug Perampanel Is a Subunit-Selective Negative Allosteric Modulator of Kainate Receptors

Article

作者: Taniguchi, Sakiko ; Stolz, Jacob R ; Swanson, Geoffrey T

Perampanel (PMP) is a third-generation antiseizure drug reported to be a potent and selective noncompetitive negative allosteric modulator of one subfamily of ionotropic glutamate receptor (iGluR), the α-amino-3-hydroxy-S-methylisoxazole-4-propionic acid receptors (AMPARs). However, the recent structural resolution of AMPARs in complex with PMP revealed that its binding pocket is formed from residues that are largely conserved in two members of another family of iGluRs, the GluK4 and GluK5 kainate receptor (KAR) subunits. We show here that PMP inhibits both recombinant and neuronal KARs, contrary to the previous reports, and that the negative allosteric modulator (NAM) activity requires GluK5 subunits to be channel constituents. PMP inhibited heteromeric GluK1/GluK5 and GluK2/GluK5 KARs at IC₅₀ values comparable to that for AMPA receptors but was much less potent on homomeric GluK1 or GluK2 KARs. The auxiliary subunits Neto1 or Neto2 also made GluK2-containing KARs more sensitive to inhibition. Finally, PMP inhibited mouse neuronal KARs containing GluK5 subunits and Neto proteins in nociceptive dorsal root ganglia neurons and hippocampal mossy fiber-CA3 pyramidal neuron synapses. These data suggest that clinical actions of PMP could arise from differential inhibition of AMPAR or KAR signaling and that more selective drugs might maintain antiseizure efficacy while reducing adverse effects.SIGNIFICANCE STATEMENT PMP is a regulatory approved antiseizure drug used for refractory partial-onset and generalized tonic-clonic seizures that acts as a selective negative allosteric modulator of AMPARs. Here, we demonstrate that PMP inhibits KARs, a second family of ionotropic glutamate receptors, in addition to AMPARs. NAM activity on KARs required GluK5 subunits or Neto auxiliary subunits as channel constituents. KAR inhibition, therefore, could contribute to PMP antiseizure action or the adverse effects that are significant with this drug. Drug discovery aimed at more selective allosteric modulators that discriminate between AMPARs and KARs could yield next-generation drugs with improved therapeutic profiles for treatment of epilepsy.