Epigenetic mechanisms re-establish access to long-term memory after neuronal loss

Abstract

The invention relates to methods and products for enhancing and improving recovery of lost memories. In particular the methods are accomplished through the increase of histone acetylation.

What is claimed is: 
     
         1 . (canceled) 
     
     
         2 . A method for accessing long-term memory in a subject having diminished access to a long-term memory comprising administering an HDAC2 inhibitor to the subject in an amount effective to reestablish access to long-term memory in the subject. 
     
     
         3 . The method of  claim 2 , wherein the long-term memory is impaired. 
     
     
         4 . The method of  claim 3 , wherein the long-term memory impairment is age related. 
     
     
         5 . The method of  claim 3 , wherein the long-term memory impairment is injury related. 
     
     
         6 . The method of  claim 2 , wherein a synaptic network in the subject is re-established. 
     
     
         7 . The method of  claim 6 , wherein re-establishing the synaptic network comprises an increase in the number of active brain synapses. 
     
     
         8 . The method of  claim 6 , wherein re-establishing the synaptic network comprises reversing neuronal loss. 
     
     
         9 .- 11 . (canceled) 
     
     
         12 . The method of claim  10 , further comprising administering a second HDAC inhibitor. 
     
     
         13 . The method of claim  10 , wherein the second HDAC inhibitor comprises a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R1 is selected from either an aryl ring system optionally substituted, or —N═R4; 
         R2 is selected from either carbon or a heteroatom that is optionally substituted with at least one hydrogen, alkyl, alkenyl, aryl, halogen, and heteroatomic groups; 
         R3 is absent or it is a carbon or heteroatom that is optionally substituted with at least one hydrogen, alkyl, alkenyl, aryl, halogen, and heteroatomic groups; 
         R4 comprises a carbon atom bound to an optionally substituted aryl, heteroaromatic, or biaryl ring system; and 
         L is 1 to 12 carbons optionally bonded to heteroatoms, alkyl, alkenyl, or aryl groups; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 13 , wherein R2 and R3 are adjacent atoms within an aromatic or heteroaromatic ring system that is optionally substituted with at least one hydrogen, alkyl, alkenyl, aryl, halogen, and heteroatomic groups. 
     
     
         15 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 13 , wherein the structure is: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 2 , further comprising altering the methylation level of one or more genes. 
     
     
         23 . The method of  claim 22 , further comprising administering a DNA methylation inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the DNA methylation inhibitor is selected from the group consisting of 5-azacytidine, 5-aza-2′deoxycytidine, 5,6-dihydro-5-azacytidine, 5,6-dihydro-5-aza-2′deoxycytidine, 5-fluorocytidine, 5-fluoro-2′deoxycytidine, and short oligonucleotides containing 5-aza-2′deoxycytosine, 5,6-dihydro-5-aza-2′deoxycytosine, and 5-fluoro-2′deoxycytosine, and procainamide, Zebularine, and (−)-egallocatechin-3-gallate. 
     
     
         25 . The method of  claim 2 , wherein the HDAC2 inhibitor is administered orally, intravenously, cutaneously, subcutaneously, nasally, imtramuscularly, intraperitoneally or intracerebroventricularly. 
     
     
         26 .- 39 . (canceled) 
     
     
         40 . A method for recapturing a memory comprising administering an HDAC2 inhibitor, in an amount effective to re-establish access to a lost memory, in a subject having Alzheimer's disease. 
     
     
         41 . A method for re-establishing a synaptic network in a subject comprising:
 administering an HDAC2 inhibitor to a human subject having chronic memory loss, in an amount effective reestablish a synaptic network in the human subject having chronic memory loss.   
     
     
         42 . The method of  claim 41 , wherein the subject has Alzheimer's disease. 
     
     
         43 . The method of  claim 41 , wherein the subject has age related memory loss. 
     
     
         44 . The method of  claim 41 , wherein the subject has injury related memory loss. 
     
     
         45 . The method of  claim 41 , wherein the subject has Parkinson's disease. 
     
     
         46 . The method of  claim 41 , wherein re-establishing the synaptic network comprises an increase in the number of active brain synapses. 
     
     
         47 . A method comprising:
 administering an HDAC2 inhibitor to a human subject having Alzheimer's disease, in an amount effective reestablish a synaptic network in the human subject.