Chemical model of a neurodegenerative disease, method for preparation and uses of same

Abstract

The invention concerns the use of pyridinium furosemide or one of the derivatives, analogues, salts, metabolites, or prodrugs thereof in the preparation of a chemical model of a neurodegenerative disease, preferably Parkinson's disease. The invention also concerns the corresponding chemical model and the uses of same, in particular in screening tests for identifying drug candidates.

We claim: 
     
         1 . A method for preparing a non-human animal model of a synucleinopathy, comprising a step of administering to a non-human animal a compound selected from the group consisting of:
 (i) furosemide pyridinium; and   (ii) a compound of formula (I)   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  represents a hydrogen atom, a C 1 -C 4  alkyl, a halogen atom, —OH, —CN, —CF 3 , —C(═O)NH 2 , —C(═O)O − , or —C(═O)O—R 5  where R 5  represents H or a C 1 -C 4  alkyl, 
 R 2  is a hydrogen atom, a halogen atom, a C 1 -C 4  alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 6  where R 6  represents H or a C 1 -C 4  alkyl, 
 R 3  is H, a halogen atom, a C 1 -C 4  alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 7  where R 7  represents H or a C 1 -C 4  alkyl, and 
 R 4  represents a hydrogen atom, —OH, or —OCH 3 , 
 
       or a pharmaceutically acceptable salt thereof, wherein the cell system is derived from nervous tissue or is of neuronal origin,
 and whereby the non-human animal model of a synucleinopathy is obtained. 
 
     
     
         2 . The method of  claim 1 , wherein the synucleinopathy is Parkinson's disease. 
     
     
         3 . The method of  claim 1 , wherein the non-human animal is selected from the group consisting of a non-human mammal, an invertebrate, and a fish. 
     
     
         4 . The method of  claim 1 , wherein the compound is furosemide pyridinium. 
     
     
         5 . A non-human model of a synucleinopathy obtained according to the method of  claim 1 . 
     
     
         6 . A method for evaluating, screening, or selecting a compound for the treatment or prevention of a synucleinopathy, said method comprising:
 a) administering to a non-human animal a compound selected from the group consisting of:   (i) furosemide pyridinium; and   (ii) a compound of formula (I)   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  represents a hydrogen atom, a C 1 -C 4  alkyl, a halogen atom, —OH, —CN, 
 —CF 3 , —C(═O)NH 2 , —C(═O)O − , or —C(═O)O—R 5  where R 5  represents H or a C 1 -C 4  alkyl, 
 R 2  is a hydrogen atom, a halogen atom, a C 1 -C 4  alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 6  where R 6  represents H or a C 1 -C 4  alkyl, 
 R 3  is H, a halogen atom, a C 1 -C 4  alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or 
 —C(═O)OR 7  where R 7  represents H or a C 1 -C 4  alkyl, and 
 R 4  represents a hydrogen atom, —OH, or —OCH 3 , 
 
         
         or a pharmaceutically acceptable salt thereof, wherein the cell system is derived from nervous tissue or is of neuronal origin, 
         b) administering to said non-human animal the test compound, and 
         c) detecting or quantifying a marker characteristic of the synucleinopathy to determine the effectiveness of the test compound for reducing the marker characteristic of the synucleinopathy, 
         wherein step b) may be implemented simultaneously, before, or after step a), or may overlap step a). 
       
     
     
         7 . The method of  claim 6 , wherein the compound is furosemide pyridinium. 
     
     
         8 . The method of  claim 7 , wherein said marker characteristic of the synucleinopathy is selected from the group consisting of a motor disorder, a degeneration of dopaminergic neurons, a sleep or arousal disorder, the intracellular accumulation of alpha-synuclein in a dopaminergic neuron, and combinations thereof in said non-human animal. 
     
     
         9 . The method of  claim 6 , wherein the cell system is a nematode, a zebrafish, or a larvae thereof. 
     
     
         10 . A kit for implementing a method for evaluating, screening, or selecting a compound intended for the treatment or prevention of a synucleinopathy, or for the preparation of a non-human model of a synucleinopathy, comprising:
 a compound selected from the group consisting of:   (i) furosemide pyridinium; and   (ii) a compound of formula (I)   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  represents a hydrogen atom, a C 1 -C 4  alkyl, a halogen atom, —OH, —CN, 
 —CF 3 , —C(═O)NH 2 , —C(═O)O − , or —C(═O)O—R 5  where R 5  represents H or a C 1 -C 4  alkyl, 
 R 2  is a hydrogen atom, a halogen atom, a C 1 -C 4  alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or —C(═O)OR 6  where R 6  represents H or a C 1 -C 4  alkyl, 
 R 3  is H, a halogen atom, a C 1 -C 4  alkyl, —OH, —CN, —C(═O)NH 2 , —CF 3 , or 
 —C(═O)OR 7  where R 7  represents H or a C 1 -C 4  alkyl, and 
 R 4  represents a hydrogen atom, —OH, or —OCH 3 , 
 
         
         or a pharmaceutically acceptable salt thereof; and 
         a non-human-animal to be administered with the compound in order to obtain said non-human model. 
       
     
     
         11 . A method for inducing in a non-human mammal one or more symptoms associated with Parkinson's disease, comprising a step of administering the compound according to  claim 1  to the non-human mammal.