Treatment of nervous system disorders using combinations of rxr agonists and thyroid hormones

Abstract

Disclosed herein are methods of treating disease with a combination of a RXR agonist and a thyroid hormone.

1 . A method of growing neurons or glial cells in vitro comprising culturing the cells in the presence of a RXR agonist, a thyroid hormone, and a neurotrophic factor or neurotrophic factor mimetic, wherein the RXR agonist is a compound having the structure of formula II: 
       
         
           
           
               
               
           
         
         wherein R is H or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of formula III: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the compound is a pharmaceutically acceptable salt. 
     
     
         4 . The method of  claim 1 , wherein the thyroid hormone is thyroxine. 
     
     
         5 . The method of  claim 1 , wherein the neurotrophic factor is brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), fibroblast growth factor, basic (bFGF), ciliary neurotrophic factor (CNTF), neurotrophic factors-4/5 (NT-4/5), insulin-like growth factor (IGF), or insulin, or a mimetic of any one of these neurotrophic factors. 
     
     
         6 . The method of  claim 5 , wherein the neurotrophic factor is GDNF. 
     
     
         7 . The method of  claim 5 , wherein the neurotrophic factor is insulin or insulin-like growth factor. 
     
     
         8 . The method of  claim 5 , wherein the neurotrophic factor is BDNF. 
     
     
         9 . The method of  claim 1 , wherein the cells are neurons. 
     
     
         10 . The method of  claim 9 , wherein the neurons are dopaminergic neurons. 
     
     
         11 . The method of  claim 9 , wherein the neurons are motor neurons. 
     
     
         12 . The method of  claim 9 , wherein the neurons are cortical neurons. 
     
     
         13 . The method of  claim 9 , wherein the neurons are hippocampal neurons. 
     
     
         14 . The method of  claim 9 , wherein the neurons are sensory neurons. 
     
     
         15 . The method of  claim 9 , wherein the neurons are optic neurons. 
     
     
         16 . The method of  claim 1 , wherein the cells are glial cells. 
     
     
         17 . The method of  claim 16 , wherein the glial cells are oligodendrocyte precursor cells. 
     
     
         18 . The method of  claim 16 , wherein the glial cells are oligodendrocytes. 
     
     
         19 . A method of treating a nervous system disorder, the method comprising administering to a human individual in need thereof a therapeutically effective amount of neurons or glial cells cultured in vitro according to the method of 1. 
     
     
         20 . A method of treating a nervous system disorder, the method comprising administering to a human individual in need thereof a therapeutically effective amount of a RXR agonist and a thyroid hormone, wherein administration of the combination of the RXR agonist and the thyroid hormone treats the disorder in the individual, wherein the RXR agonist is a compound having the structure of formula II: 
       
         
           
           
               
               
           
         
         wherein R is H or lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt thereof; 
         wherein the combination of RXR agonist and thyroid hormone causes a greater improvement in the disorder than the RXR agonist or thyroid hormone alone.