Suppression of glial fibrillary acidic protein

Abstract

Provided herein are methods of decreasing glial fibrillary acidic protein (GFAP) levels in a cell. Such methods include administering an effective amount of a GFAP lowering compound to the cell. Also provided are compounds useful for the treatment of Alexander disease in subjects at risk of or diagnosed with Alexander disease and methods for the identification of such compounds.

What is claimed is: 
     
         1 . A method of decreasing glial fibrillary acidic protein (GFAP) levels in a cell comprising:
 administering an effective amount of GFAP lowering compound to the cell;   wherein the GFAP lowering compound is selected from the group consisting of c-pendant amino tricyclic compounds; quinone compounds; triterpene derivatives; and polyphenol compounds.   
     
     
         2 . The method of  claim 1  wherein the GFAP lowering compound exhibits an hGFAP promoter luciferase reduction of at least about 10%. 
     
     
         3 . The method of  claim 1  wherein the GFAP lowering compound exhibits a cell-based GFAP protein level reduction of at least about 6%. 
     
     
         4 . The method of  claim 1  wherein the GFAP lowering compound has an MTDcc of at least about 10 μM. 
     
     
         5 . The method of  claim 1 , wherein the GFAP lowering compound comprises clomiprimine. 
     
     
         6 . The method of  claim 1 , wherein the GFAP lowering compound comprises betulinic acid and/or a betulinic acid derivative. 
     
     
         7 . The method of  claim 1 , wherein the GFAP lowering compound comprises epigallocatechin 3,5-digallate (EGCDG). 
     
     
         8 . The method of  claim 1 , wherein the GFAP lowering compound comprises amitriptyline. 
     
     
         9 . The method of  claim 1 , wherein the cell is in a human subject. 
     
     
         10 . The method of  claim 1 , wherein the GFAP lowering compound is selected from the group consisting of diaziquone, clomipramine, chrysophanol, amitriptyline, chlorprothixene, EGCDG, tamoxifen, mundoserone, amlodipine, embelin, thioridazine, ritanserin, irigenol, fluccinonide, hexetidine, estradiol benzoate, ketotifen, clobetasol propionate, colecalciferol, fluphenazine, pyrogallin, kanamycin and mixtures thereof. 
     
     
         11 . The method of  claim 1 , wherein the GFAP lowering compound is selected from the group consisting of diaziquone, clomipramine, chrysophanol, amitriptyline, tamoxifen, amlodipine, embelin, thioridazine, ritanserin, ketotifen, kanamycin, 4-acetamidophenyl salicylate, terfenadine and mixtures thereof. 
     
     
         12 . The method of  claim 1 , wherein the GFAP lowering compound is selected from the group consisting of diaziquone, clomipramine, chrysophanol, amitriptyline, chlorprothixene, EGCDG, mundoserone, amlodipine, ritanserin, irigenol, fluccinonide, hexetidine, estradiol benzoate, ketotifin, clobetasol propionate, colecalciferol, pyrogallin, kanamycin, azinphos methyl, 4-acetamidophenyl salicylate, oxotremorine, ritodrine, NPPB, chloramphenicol, phosphocreatine, betulinic acid, betulinic acid derivatives, methylnorlichexanthone, coumophos and mixtures thereof. 
     
     
         13 . A method for decreasing the amount of GFAP in a subject comprising:
 administering a therapeutically effective amount of a GFAP lowering compound to the subject.   
     
     
         14 . The method of  claim 13 , wherein the subject is a human subject. 
     
     
         15 . The method of  claim 13 , wherein the administering the GFAP lowering compound decreases Rosenthal fibers in the subject. 
     
     
         16 . The method of  claim 13 , wherein the subject has been diagnosed with or is at risk of gliosis. 
     
     
         17 . The method of  claim 13 , wherein the GFAP lowering compound is selected from the group consisting of diaziquone, clomipramine, chrysophanol, amitriptyline, chlorprothixene, EGCDG, mundoserone, amlodipine, ritanserin, irigenol, fluccinonide, hexetidine, estradiol benzoate, ketotifin, clobetasol propionate, colecalciferol, pyrogallin, kanamycin, azinphos methyl, 4-acetamidophenyl salicylate, oxotremorine, ritodrine, NPPB, chloramphenicol, phosphocreatine, betulinic acid, methylnorlichexanthone, coumophos and mixtures thereof. 
     
     
         18 . A method of treating Alexander disease comprising:
 administering to a subject at risk of or diagnosed with Alexander disease a therapeutically effective amount of a GFAP lowering compound.   
     
     
         19 . The method of  claim 18 , wherein the administering decreases one or more symptoms selected from the group consisting of:
 a) the intensity of megalencelphaly associated with Alexander disease;   b) the amount of Rosenthal fibers;   c) the frequency of seizures; and   d) the intensity of seizures.