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Applications of tiagabine in preparing medicines for treating dopaminergic neuron injuries

A neuron damage and dopaminergic technology, applied in the field of antiepileptic drug tiagabine, can solve the problems of high cost and decreased efficacy, and achieve the effect of protecting dopaminergic nerve cells

Inactive Publication Date: 2015-03-18
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Practice has shown that these treatment strategies have limitations. Among them, after about 6 years of use of levodopa, the curative effect will decline, and most PD patients are often accompanied by serious complications such as "switching" phenomenon and dyskinesia; while deep brain stimulation (DBS) treatment has certain surgical risks and is expensive

Method used

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  • Applications of tiagabine in preparing medicines for treating dopaminergic neuron injuries
  • Applications of tiagabine in preparing medicines for treating dopaminergic neuron injuries
  • Applications of tiagabine in preparing medicines for treating dopaminergic neuron injuries

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: BV2 cells were cultured, treated with drugs, and the activity of NF-κB in the cells was analyzed

[0046] 1) NF-κB nuclear localization study: BV2 microglial cells were cultured in DMEM / F12+5% fetal bovine serum medium; PBS; LPS (1 μg / ml); Tiagabine (50 μM); Tiagabine pre-administration were given according to groups After 1 hour of LPS administration, the nuclear localization of NF-κB (p65 subunit) was observed by immunofluorescence staining and laser confocal imaging techniques; figure 1 Shown in A: In the resting state, NF-κB (p65 subunit) is mainly localized in the cytoplasm; 1 hour after LPS stimulation, the nuclear localization of NF-κB increases, indicating that the pathway is activated; pre-administration of Tiagabine can reduce The nuclear import of NF-κB inhibits the activation of inflammatory pathways; while single administration of Tiagabine has no effect on the nuclear localization of NF-κB.

[0047] 2) Cellular NF-κB activity was detected by a ...

Embodiment 2

[0048] Example 2: Collect the conditioned medium of BV2 cells, add the cultured human dopaminergic cell line SH-SY5Y cells, and analyze the viability of SH-SY5Y cells

[0049] BV2 microglial cells were given PBS; LPS (1 μg / ml); Tiagabine (50 μM); Tiagabine was pre-administered for 1 hour + LPS, and 24 hours later, the medium of each group was added to SH-SY5Y cells for conditional culture. After 24 hours, the activity of SH-SY5Y cells was detected by MTT method; figure 2 As shown, the viability of conditionally cultured SH-SY5Y cells in the LPS stimulation group was significantly decreased; pre-administration of different doses of Tiagabine (5, 10, 50, 100 μM) before LPS stimulation could significantly improve the viability of conditionally cultured SH-SY5Y cells , but 500μM Tiagabine showed significant toxicity to the cells, **P<0.01 compared with the control group; #p<0.05, ##p<0.01 compared with the LPS group.

Embodiment 3

[0050] Example 3: Intraperitoneal injection of MPTP or substantia nigra stereotaxic injection of LPS, combined with Tiagabine pre-administration, analysis of microglial activation

[0051] 1) Microglia activation after intraperitoneal injection of drugs in mice: C57BL / 6 mice aged 10-14 weeks were used in the experiment, and the experiment was divided into three groups: normal saline control group; MPTP group; co-administration of Tiagabine and MPTP Group. MPTP acute model establishment method: intraperitoneal injection of MPTP·HCl (20 mg / kg) every 2 hours, a total of 4 times; normal saline control group intraperitoneal injection of the same volume of normal saline; Tiagabine (1 mg / kg) was injected intraperitoneally 1 hour before. On the second day after the establishment of the model, the brains of the mice were perfused, fixed, dehydrated, and frozen for sectioning. The striatum and substantia nigra were stained for the microglial marker Iba1 by immunofluorescent staining, a...

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Abstract

The invention relates to the fields of neurology, geriatrics and neuropharmacology in biomedicine, and particularly relates to the new medicinal applications of antiepileptic drug tiagabine. The applications disclosed by the invention are based on the pathological features of Parkinson disease and the inhibitory effect of GABA in central nervous system and immune system, and the results of experiments in a neurotoxin-induced mouse model with Parkinson disease show that tiagabine, a gamma-aminobutyric acid transporter antagonist is used for protecting dopaminergic neuron by enhancing the system activity of gamma-aminobutyric acid and inhibiting neuroinflammation, thus having a treatment function on Parkinson disease. Tiagabine can be used for preparing medicines for treating dopaminergic neuron injuries and medicines for treating Parkinson disease.

Description

technical field [0001] The present invention relates to the fields of neurology, geriatrics and neuropharmacology in biomedicine, in particular to the new medicinal use of the antiepileptic drug Tiagabine, and more specifically to the use of Tiagabine in the preparation and treatment of dopaminergic neurons The use of impairment drugs and their protective effects in Parkinson's disease. Background technique [0002] Studies have shown that Parkinson's disease (PD) is a chronic degenerative disease of the central nervous system, and its incidence increases with age. According to reports, the incidence of PD among people over 65 years old in my country is about 1.5 %, with the development of population aging process, the number of patients with Parkinson's disease is increasing year by year. At present, the exact cause of Parkinson's disease is still unclear. The general view in the industry is that its cause is caused by environmental factors, genetic factors, or both (Vila M...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4535A61P25/16A61P25/00
CPCA61K31/4535A61K2300/00
Inventor 黄芳刘杰
Owner FUDAN UNIV
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