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New use of inhibitor of cystine-glutamate transporter

一种转运蛋白、抑制剂的技术，应用在胱氨酸-谷氨酸转运蛋白抑制剂领域，能够解决不确定作用等问题

Active Publication Date: 2018-02-23
CHINA MEDICAL UNIVERSITY(TW)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These problems cause system x c - Uncertain role in addiction

Method used

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  • New use of inhibitor of cystine-glutamate transporter
  • New use of inhibitor of cystine-glutamate transporter
  • New use of inhibitor of cystine-glutamate transporter

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0065] Instance 1 system x c - effect on addiction

[0066] for trying to get system x c - Insights into the role of addiction, first using a free-choice two-bottle drinking behavior test to measure alcohol self-administration and preference. xCT knockout (KO) mice consumed much less alcohol than wild-type (WT) mice ( figure 1 A). Furthermore, alcohol preference in xCT KO mice was much lower than in WT mice ( figure 1 B). There was no significant difference in saccharin or quinine preference between xCT KO mice and WT mice ( figure 1 C), which indicates that alcohol avoidance in xCT KO mice does not stem from taste neophobia. The water consumption of the two genotypes was not significantly different throughout the experiment ( figure 1 D). To induce alcohol-dependent mice, xCT KO mice and WT mice were subjected to long-term alcohol exposure by feeding an alcoholic liquid diet for 14 days and then presented during the alcohol acquisition period using 2 vials (one cont...

example 2

[0067] System x in Example 2 Alcohol Dependence c - The therapeutic potential of manipulation

[0068] Research Systemx c - Therapeutic Potential of Manipulation in Alcohol Dependence, Using the Blocking System x c - Sulfasalazine, sorafenib and regorafenib (Buckingham S.C. et al., Glutamate release-induced epilepsy activity in primary brain tumors. Nature Medicine, 2011.17(10): pp. 1269-74 ; Zhong W.J. (Chung, W.J.) et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. Journal of Neuroscience, 2005.25 (31: No. 7101-10 pp) to treat alcohol-dependent mice. Compared with the control vehicle, sulfasalazine, sorafenib and regorafenib significantly reduced daily alcohol consumption (DMSO) during free choice drinking ( figure 2 B). These results show that the system x c - Alcohol addiction can be ameliorated by pharmacological inhibition of its inhibitors (ie, sorafenib, regorafenib, and sulfasalazine).

example 3

[0069] Example 3 Improved Analysis of Cocaine Addiction and Alcohol Addiction

[0070] for test system x c - Whether to play the same role in other substance use disorders, xCT KO mice and WT mice were forced to receive intraperitoneal injection of cocaine for 7 days and then transferred to use 2 vials (one containing diluted cocaine and the other containing normal water) for 8 days in a free-choice drinking model. Like alcohol-dependent mice, WT mice had cocaine-preferring behavior and displayed craving behavior after chronic cocaine exposure ( image 3 A). However, xCT KO mice attempted to drink normal water, thus indicating systemic x c - A genetic defect suppresses cocaine addiction. Additionally, cocaine-dependent WT mice were treated daily with sulfasalazine or vehicle following chronic cocaine exposure. Surprisingly, compared with vehicle treatment, sulfasalazine treatment completely suppressed cocaine preference and craving behavior ( image 3 B). These result...

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Abstract

The agents that inhibit system x c - provide the therapeutic intervention in substance-related and addictive disorders and the treatment and / or prevention in substance-mediated brain damage, and confirm that system x c -is a promising therapeutic target for substance-induced addiction and brain damage.

Description

technical field [0001] The present invention relates to novel uses of cystine-glutamate transporter inhibitors, and in particular to methods of ameliorating substance-related and addictive disorders or brain damage induced by substance-related and addictive disorders. Background technique [0002] Substance use disorders produce addiction and brain damage without proven successful treatments, largely due to a lack of understanding of their pathobiology. Dependence on addictive drugs causes major health problems worldwide. For example, alcohol abuse and alcohol dependence can cause liver disease, pancreatic and kidney disease, heart disease, increased incidence of many types of cancer, insomnia, depression, anxiety and even suicide. Nicotine addiction is associated with disease states such as leukemia, cataracts and pneumonia; it is the cause of approximately one-third of all cancer deaths, primarily lung cancer. Another major health problem is caused by cocaine abuse. Phy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/63A61K31/44A61P25/36A61P25/32
CPCA61K31/44A61K31/655A61P25/36A61P25/32A61K31/4402A61K45/06
Inventor 谢佳宏
Owner CHINA MEDICAL UNIVERSITY(TW)
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