Application of neuregulin 1 and acceptor thereof as target for preparing and screening anti-epileptic drugs

A technology of neurotongulin and epilepsy, which is applied in the field of biotechnology and medicine, and can solve the problem of not finding an anti-epileptic target

Inactive Publication Date: 2013-05-08
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In summary, although some genetic and epidemiological causes of epilepsy are currently known, people i

Method used

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  • Application of neuregulin 1 and acceptor thereof as target for preparing and screening anti-epileptic drugs
  • Application of neuregulin 1 and acceptor thereof as target for preparing and screening anti-epileptic drugs
  • Application of neuregulin 1 and acceptor thereof as target for preparing and screening anti-epileptic drugs

Examples

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preparation example Construction

[0216] HEK293 cell culture and preparation of recombinant protein

[0217]The preparation method of the recombinant polypeptide at the extracellular end of ErbB4 (ecto-ErbB4) can be referred to from the literature (Woo, R.S., et al. Neuregulin-1enhances depolarization-induced GABA release. Neuron 2007, 54: 599-610). Briefly, the HEK293 cell line was cultured by conventional methods, and then the entire extracellular end sequence of ErbB4 (GenBank accession number NM_005235.2; amino acid sequence 1-659) was expressed and fused with F C HEK293 cells were co-transfected with the fragmented pC4-B4Ex / Fc plasmid and the pEGFP-C1 plasmid (Clontech) containing the neomycin resistance gene at a ratio of 10:1. Use G418 (0.4mg / ml) to select resistance-positive cells, expand them, culture the cells in 2% low immunoglobulin fetal bovine serum, collect the medium, and use it to purify the ecto secreted in the medium -ErbB4. The collected cultures were uniformly frozen and stored in a -80°...

Embodiment 1

[0244] Example 1. Influence of epileptic seizure activity on NRG1-ErbB4 signaling pathway

[0245] Epileptic activity can be induced by a variety of stimuli, such as structural damage, electrical stimulation, or chemical agents, which trigger a series of signaling cascades that ultimately lead to the expression of a large number of genes, including not only some immediate early genes, but also A number of nutritional factors, all of which can further affect the structural and functional properties of the brain. The inventors first observed whether temporal lobe epilepsy activity up-regulates the gene transcription level of Nrg1. The epileptic seizures were induced on the rat electrical stimulation ignition model, and then the changes of Nrg1 mRNA levels were detected by reverse transcription PCR, fluorescent real-time quantitative PCR and in situ hybridization. significantly increased, reaching a peak 3 hours after stimulation, about 1.50±0.04 times the background level, and ...

Embodiment 2

[0249] Example 2, Effects of NRG1, ecto-ErbB4 and PD158780 on ErbB4 Phosphorylation

[0250] The inventors used three different strategies to pharmacologically intervene the NRG1-ErbB4 signaling system in experimental animals to test its role in the development of epilepsy: one was intracerebroventricular injection of artificially recombined NRG1 functional polypeptides (containing the EGF function of NRG1 region) to increase the level of NRG1 active form in the brain; the second is to use ecto-ErbB4 (in vitro recombinant polypeptide of the extracellular segment of ErbB4 receptor) to bind endogenous NRG1 in the brain to neutralize and reduce NRG1 in the brain, Prevent it from continuing to bind and activate endogenous receptors in the body; the third is to use ErbB4 phosphorylation inhibitor PD158780 to inhibit the kinase activity of ErbB4 (see Examples 3 and 4 for details). First, the inventors verified their effects using NRG1 recombinant protein, ecto-ErbB4 and ErbB4 inhibi...

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Abstract

The invention relates to an application of neuregulin 1 (NRG1) and acceptor thereof as a target for preparing and screening anti-epileptic drugs. The application of NRG1 for inhibiting the development and progression of epilepsy by activating leukemia virus oncogene homolog 4 (ErbB4) of bird red blood cells in inhibitory neurons in the brain is proposed for the first time; and novel target is provided for effective prevention, control or treatment of the epilepsy.

Description

technical field [0001] The invention belongs to the fields of biotechnology and medicine, and more specifically, the invention relates to the use of neurotonin 1 and its receptor as a target for preparing or screening antiepileptic drugs. Background technique [0002] Epilepsy is a chronic and destructive neurological disease in which the sudden abnormal discharge of brain neurons leads to transient brain dysfunction. Temporal lobe epilepsy is the most common one. Due to the different parts involved in abnormal discharge neurons, Can manifest as seizures of motor, sensory, autonomic, conscious, and mental disturbances. Epilepsy (Epilepsy) is a kind of common disease that endangers human health, and its sickness rate accounts for about 1-2% all over the world, and it also lacks effective therapeutic means (McNamara, J.O., Huang, Y.Z.& Leonard, A.S. Molecular signaling mechanisms underlying epileptogenesis. Sci STKE 2006, 2006: 12; Morimoto, K., Fahnestock, M. & Racine, R.J. ...

Claims

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Application Information

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IPC IPC(8): A61K38/17A61K45/00G01N33/569G01N33/53C12Q1/68A61P25/08
Inventor 熊志奇谭国鹤刘媛媛
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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