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Effect of N-methyl-D-asparagic acid acceptor in epilepsy generation

A receptor and anti-epilepsy technology, applied in the fields of biotechnology and medicine, can solve the problem of not being able to know NMDA receptors

Inactive Publication Date: 2008-07-23
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it is now known that overactivation of NMDA receptors is the cause of certain neurological diseases such as epilepsy, it is still unknown to those skilled in the art which subunits of NMDA receptors are truly pathogenic.

Method used

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  • Effect of N-methyl-D-asparagic acid acceptor in epilepsy generation
  • Effect of N-methyl-D-asparagic acid acceptor in epilepsy generation
  • Effect of N-methyl-D-asparagic acid acceptor in epilepsy generation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0177] Example 1 Different effects of NR2A and NR2B subunits on BDNF expression

[0178] Bicuculline, an antagonist of GABAA receptor (γ-aminobutyric acid type A receptor), can increase the transmission of excitatory synapses, thereby significantly increasing the expression level of BDNF mRNA, and non-selective NMDA receptors The body antagonist MK801 can block the increase of BDNF mRNA induced by Bicuculline, suggesting that neuronal activity-dependent BDNF expression requires the activation of synaptic NMDA receptors. Mature hippocampal neurons mainly express NR1, NR2A or NR2B subunits. In order to detect the expression of BDNF that different subunits of NR2A or NR2B depend on neuron activity, the inventors used two antagonists NVP-AAM077 and Ifenprodil. Among them, NVP-AAM077 is considered to have a relatively strong selective inhibitory effect on NR1 / NR2A receptors at low concentrations, and Ifenprodil has a selective inhibitory effect on NR1 / NR2B receptors.

[0179] The...

Embodiment 2

[0189] Example 2 Effects of NR2A and NR2B subunits on NMDA-mediated phosphorylation of ERK1 / 2

[0190] Extracellular signal-regulated kinase 1 / 2 (ERK1 / 2) plays an important role in cell proliferation, differentiation and survival. Therefore, the present inventors examined the role of NR2A and NR2B in NMDA receptor-mediated activation of ERK1 / 2.

[0191] Activation of NMDA receptors on cells with 50uM Bicuculline resulted in phosphorylation of ERK1 / 2, Ifenprodil (30nmol) inhibited phosphorylation of ERK1 / 2, but NVP-AAM077 (4nmol) had no effect ( figure 2 A, B). Similarly, expression of NR2Btail in hippocampal neurons by transgenic method can also inhibit the phosphorylation of ERK1 / 2, while NR2Atail and EGFP have no effect ( figure 2 C, D).

[0192] The inventors used immunohistochemical methods in vivo to detect that the phosphorylation level of ERK1 / 2 in the hippocampus of rats was significantly increased 3 hours after epilepsy, while MK801 and Ifenprodil could significa...

Embodiment 3

[0194] Example 3 Different roles of NR2A and NR2B in epilepsy generation

[0195] The inventors first tested the effects of different NMDA receptor antagonists on the generation of epilepsy in the Kindle epilepsy model, and set up the Kindle epilepsy model group and the Pilocarpine epilepsy model group. The processing flow of the two groups is shown in Figure 3A. The criterion for judging is mainly to observe the number of electrical stimulations required by each group to achieve the same epileptic behavior level during the whole ignition process.

[0196] Ventricular administration of NMDA receptor antagonists had no effect on afterdi scharge threshold ( Figure 9 D). Compared with the normal saline administered to the ventricles of the control group, intraventricular administration of the NMDA receptor non-selective antagonist MK801 30 min before each electrical stimulation could delay the development of epilepsy in the lit epilepsy model (Fig. 3B). These studies demonstrate...

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Abstract

The invention discloses an application of NMDA receptor NR2A subunit for selecting anti-epilepsy latent material and the application of antagonist, inhibitor or antagonist of NMDA receptor NR2A subunit for preparing the drug to treat epilepsy. The invention provides that the NR2A subunit of NMDA receptor is the subunit participating epilepsy generation or development, thereby providing a drug target for preventing or treating epilepsy.

Description

technical field [0001] The invention belongs to the fields of biotechnology and medicine, and specifically relates to the application of N-methyl-D-aspartate receptor NR2A subunit and its antagonist, inhibitor or blocker. Background technique [0002] Epilepsy is a chronic disease in which the sudden abnormal discharge of brain neurons leads to transient brain dysfunction. Due to the different parts involved in the abnormal discharge of neurons, it can be manifested as seizures of motor, sensory, autonomic, conscious and mental disorders. Epilepsy (Epilepsy) is a common disease that endangers human health. At present, there is no effective means for the treatment of epilepsy in this field. [0003] N-Methyl-D-Aspartate (NMDA) Receptor (NMDA receptor for short) is an important excitatory glutamate receptor in the mammalian nervous system. Many physiological and pathological processes in the body, glutamate excitotoxicity caused by excessive activation of NMDA receptors are ...

Claims

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Application Information

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IPC IPC(8): G01N33/68G01N33/53A61K49/00A61K31/375A61K39/395A61P25/08
Inventor 熊志奇段文虎陈迁
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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