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Application of specific inhibitor of SHH signaling pathway

A signal pathway and inhibitor technology, applied in the field of biomedicine, can solve problems such as incompletely clear functions

Inactive Publication Date: 2015-07-01
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] However, although the SHH signaling pathway remains widely expressed in the adult brain, its role is not fully understood

Method used

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  • Application of specific inhibitor of SHH signaling pathway
  • Application of specific inhibitor of SHH signaling pathway
  • Application of specific inhibitor of SHH signaling pathway

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1, SHH signaling pathway affects glutamate level

[0079] In order to study whether the SHH pathway affects and extracellular glutamate levels, the inventors used high performance liquid chromatography (HPLC) to detect the extracellular glutamate in hippocampal neurons cultured in vitro (isolated rat hippocampal primary culture). Concentration, found that adding SHH (purchased from Sigma) can promote the accumulation of glutamate, and this effect can be inhibited by the inhibitor Cyclopamine (cyclopamine, purchased from Sigma) of this signaling pathway ( figure 1 A, where SHH concentration is 500ng / ml, Cyclopamine 10μM).

[0080] As the concentration of SHH increases, the level of glutamate increases simultaneously, and the level of glutamate reaches the peak when SHH reaches 500-1000ng / ml ( figure 1 B), its elevated level is similar to the effect of TBOA ( figure 1 C, wherein the concentration of SHH is 500 ng / ml, and the concentration of TBOA is 100 μM).

...

Embodiment 2

[0082] Example 2, Cyclopamine and GDC-0449 can inhibit the epileptiform discharge of primary cultured hippocampal neurons

[0083] In order to study the role of endogenous SHH, the present inventors explored the conditions of SHH release. The experimental results of ELISA showed that the neurons cultured in vitro were stimulated with magnesium ion-free extracellular fluid for 15 minutes, and a significant increase in the secretion of SHH could be detected in 30 minutes and 60 minutes ( figure 2 A).

[0084] Similarly, the present inventors found that when the external fluid with GABA inhibitor (Picrotoxin) and high potassium ion content was administered simultaneously during incubation, the increase of SHH secretion could also be detected in the external fluid from 15 minutes ( figure 2 B).

[0085] Further, the method of the whole cell patch clamp recording of the present invention, in the pre-incubation without Mg 2+ After 30 minutes of external fluid or PTX, high conce...

Embodiment 3

[0086] Example 3, Cyclopamine can reduce the amplitude of the spike potential of hippocampal neuron groups in acute brain slices of rats

[0087] In order to explore whether cyclopamine can inhibit epileptogenesis under close to in vivo conditions, the present inventors adopted the method of electrophysiological recording of acute isolated brain slices of adult rats. First, add Picrotoxin (100μm) to the artificial cerebrospinal fluid of the brain slices, and increase the concentration of potassium ions (6.5mM) to induce seizures. ELISA results show that there is a large amount of SHH released. In the same context, the inventors recorded stimulation-induced multilevel group spikes extracellularly in the CA1 cell body layer of the hippocampus. After perfusion with Cyclopamine, the amplitudes of group spikes all decreased. The magnitude of the first group spike potential was counted, and there was a significant difference after 15 minutes of perfusion ( Figure 4 ).

[0088] T...

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Abstract

The present invention relates to the application of a specific inhibitor for an SHH signaling pathway. Disclosed for the first time are that the SHH signaling pathway and excitability of neural networks have a close relationship and are involved in the formation and development of epilepsy, and are thus able to act as drug targets for developing drugs for improving or treating epilepsy. Also disclosed is a specific inhibitor for SHH signaling pathway capable of delaying epileptogenesis and being used as a drug for improving or treating epilepsy.

Description

technical field [0001] The invention belongs to the field of biomedicine; more specifically, the invention relates to the application of specific inhibitors of SHH signaling pathway. Background technique [0002] Epilepsy is a chronic disease in which the sudden abnormal discharge of brain neurons leads to transient brain dysfunction. Worldwide, about 1% of the population suffers from epilepsy. Epilepsy has become the second most common disease in neurology after headache in China. The etiology of epilepsy is very complex, including genetic factors, abnormal brain development, brain damage and so on. In general, the onset of epilepsy is caused by a large accumulation of the excitatory neurotransmitter glutamate due to an imbalance between inhibition and excitability of the neural network. The treatment of epilepsy mainly consists of drug therapy and surgical excision of the lesion. About 30% of patients with temporal lobe epilepsy are insensitive or resistant to existing...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/58A61K31/4402A61P25/08G01N33/48G01N33/15
CPCA61K31/58A61K31/4418A61K31/4402A61P25/08
Inventor 王以政冯昇杰马韶蓉贾彩霞
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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