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In vivo screening method of therapeutic agent for memory/learning dysfunctions by schizophrenia

a technology for schizophrenia and memory/learning dysfunction, applied in the field of in vivo screening of therapeutic agents, can solve the problems of selective and serious damage to certain memory functions, insufficient drug efficacy of these existing drugs, and most serious damage to reference memory, so as to improve cognitive dysfunction activity, improve cognitive dysfunction, and improve cognitive function.

Inactive Publication Date: 2007-07-12
SUMITOMO DAINIPPON PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides an in vivo screening method for identifying therapeutic agents for memory / learning dysfunctions caused by schizophrenia. This method involves using an animal model with glutamic acid NMDA type receptor hypofunction to evaluate the efficacy of potential therapeutic agents. The method is simple, reproducible, and can predict the clinical effectiveness of existing therapeutic agents. The invention also provides a therapeutic agent that can improve memory / learning dysfunctions in schizophrenia patients. The therapeutic agent can be selected by screening a library of compounds using the animal model."

Problems solved by technology

Schizophrenia is associated with various cognitive dysfunctions such as attention, memory, learning, executive functions, but it is reported that among these functions, especially a certain memory function is selectively and seriously damaged.
It is reported that in schizophrenia, the declarative memory including both of the working memory and the reference memory is selectively damaged, and further, among them, the damage of the reference memory is most serious.
However, the drug efficacy of these existing drugs are not sufficient enough, and hence, it has been discussed that it is important to develop a therapeutic agent for cognitive dysfunctions by schizophrenia (cf., Science 299: 350-351 (2003)).
However, it is considered that an animal model for cognitive dysfunctions by schizophrenia satisfying such requirements is quite limited at the moment.

Method used

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  • In vivo screening method of therapeutic agent for memory/learning dysfunctions by schizophrenia

Examples

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example 1

(Method)

[0027] Wistar male rats (7 weeks old) were used. Haloperidol (a typical anti-psychotic agent), clozapine, quetiapine, risperidon, olanzapine or aripiprazole (atypical anti-psychotic agent), or lurasidone being under development as a novel anti-psychotic agent was suspended in a 0.5% methyl cellulose (MC) and the resultant suspension was used as a test compound. Serotonin 5-HT 1A receptor antagonist WAY-100635 or noradrenaline α2 receptor antagonist 1-PP was dissolved in a physiological saline solution (Otsuka Pharmaceutical Co., Ltd.) and used as a test compound. As an NMDA type receptor antagonist, MK-801 hydrogen maleate (SIGMA-ALDRICH M-107) was dissolved in a physiological saline solution (Otsuka Pharmaceutical Co., Ltd.). A test compound (0.3 to 10 mg / kg) or a 0.5% MC or a physiological saline solution as a control was orally or interperitoneally administered to the animals one hour prior to the training session of the passive avoidance task, and MK-801 (0.05 mg / kg) o...

example 2

[0034] In the procedures of Example 1, PCP HCl (0.75 mg / kg) was subcutaneously administered instead of MK-801 (0.05 mg / kg) to animals prior to both of the training session and the testing session of the memory / learning task to induce memory / learning dysfunctions, and the memory / learning dysfunction improving activity of a test compound can be evaluated.

example 3

[0035] The memory / learning dysfunction improving activity of a test compound can be evaluated under the exactly same conditions as those in Examples 1 and 2, except that ketamine is used instead of MK-801 or PCP HCl.

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Abstract

A method of evaluating memory / learning functions with the use of a model with glutamic acid N-methyl-D-aspartate (NMDA) type receptor hypofunction as an animal model for schizophrenia and with the use of reference memory task, wherein there has been found concrete means for detecting any differences in activity between typical anti-psychosis drugs and atypical anti-psychosis drugs is found. An in vivo animal model for screening of a therapeutic agent for improving cognitive dysfunction by schizophrenia is provided.

Description

TECHNICAL FIELD [0001] The present invention relates to an in vivo screening method of a therapeutic agent for improving memory / learning dysfunctions by schizophrenia. BACKGROUND ART [0002] Glutamic acid is a most popular excitatory neurotransmitter in the central nervous system, and the receptors thereof are classified broadly into an NMDA type, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) type, a kainate type, and a metabotropic type. It is revealed that the NMDA type receptor plays an important role in the completion of the long-term potentiation (LTP), which is an electrophysiologically basal process of the memory / learning functions (cf., Science 285: 1870-1874 (1999)). At the animal level, it is known that an NMDA receptor antagonist may induce memory / learning dysfunctions in various memory / learning tasks such as a passive avoidance response, a radial maze, a T or Y maze, a water maze, a place or object recognition, an autoshaping learning task, and a lever-pressin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00A61K31/445A61K31/496A61K31/551A61K31/554A61K45/00A61P25/28A61P43/00C07D211/32C07D243/10C07D281/14C07D417/12G01N33/15G01N33/50
CPCA61K31/445A61K31/496A61K31/5513A61K31/554A61K49/0008G01N33/5088A61K31/4515A61K31/519C07D417/12A61P25/18A61P25/28A61P43/00
Inventor ISHIYAMA, TAKEO
Owner SUMITOMO DAINIPPON PHARMA CO LTD
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