Compositions and methods for promoting nerve regeneration

Abstract

Neurite outgrowth and nerve regeneration are promoted by disruption of the steroid receptor complex and stimulation of MAP kinase/kinase activity. This disruption can take the form of disruption of the physical assembly or function of the steroid receptor complex, such as the mature complex or a precursor of the mature complex that is required for assembly of the mature complex. Geldanamycin and its analogs, bastadin and members of the bastadin family, and radicicol and its analogs, as well as FKBP-52 antibody, are shown to disrupt the complex and promote nerve growth. Assays for finding neurotrophic compounds, as well as compounds found by these assays, pharmaceutical compositions into which they are incorporated, and methods of treating subjects having neuronal dysfunction caused by injury or desease are disclosed. Any of these compounds can be used in combination with a therapeutically effective amount of heat, such as heat applied locally to an area where nerve growth is desired, or systemically in an organism in which neurite growth is desired. Alternatively, these compounds can he used in association with a template, such as a tubular member that defines an anatomic pathway along which nerve regeneration is desired (particularly around transected or partially transected nerve).

1 - 30 . (Canceled)  
     
     
         31 . A method for stimulating nerve cell growth in a subject comprising administering to the subject a therapeutically effective amount of a bastadin subunit or an analog thereof that stimulates nerve cell growth.  
     
     
         32 . The method of claim  1  wherein the bastadin subunit is a bromotyrosine or an analog thereof or a bromotyrosine dimer or an analog thereof.  
     
     
         33 . The method of  claim 32 , wherein the bastadin subunit is a bromotyrosine dimer or an analog thereof.  
     
     
         34 . The method of  claim 31 , wherein the bromotryosine dimer is a hemibastadin or analog thereof.  
     
     
         35 . The method of  claim 34 , wherein the hemibastadin is a hemibastadin having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X and Y are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         36 . The method of  claim 35 , wherein the hemibastadin is hemibastadin 1, 2 or 3, or an analog thereof.  
     
     
         37 . The method of  claim 33 , wherein the bromotyrosine dimer or analog thereof is a hemibastadinol or analog thererof.  
     
     
         38 . The method of  claim 37 , wherein the hemibastadin is a hemibastadinol having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X and Y are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         39 . The method of  claim 38 , wherein the hemibastadin is hemibastadinol 1, 2 or 3, or an analog thereof.  
     
     
         40 . The method of  claim 32 , wherein the bastadin subunit is a bromotryosine or analog thereof.  
     
     
         41 . The method of  claim 40 , wherein the bromotryosine or analog thereof has the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X is selected from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         42 . The method of  claim 41 , wherein the bastadin subunit is the 3-bromotyramine amide of oxalic acid amide.  
     
     
         43 . The method of  claim 31  further comprising applying a therapeutically effective amount of heat to an area where nerve cell growth is desired, wherein the therapeutically effective amount of heat enhances nerve growth.  
     
     
         44 . The method of  claim 31 , further comprising providing a template in an area where nerve growth is desired, wherein the template provides a pathway along which nerve growth is desired.  
     
     
         45 . The method of  claim 44 , wherein the template is a tubular member that defines an anatomical pathway along which nerve growth is desired.  
     
     
         46 . The method of  claim 44 , wherein the template is placed between opposing ends of a transected or partially transected nerve.  
     
     
         47 . The method of  claim 41  further comprising applying to the template a therapeutically effective amount of heat, wherein the therapeutically effective amount of heat enhances nerve growth.  
     
     
         48 . The method of  claim 31  further comprising administering a second neurotrophic agent other than the bastadin subunit or analog thereof.  
     
     
         49 . The method of  claim 48 , wherein the second neurotrophic agent is NGF, IGF-1, α-FGF, β-FGF, PDGF, BDNF, CNTF, GDNF, NT-3, NT4/5, or a mixture thereof.  
     
     
         50 . The method of  claim 48  further comprising applying a therapeutically effective amount of heat to an area where nerve cell growth is desired, wherein the therapeutically effective amount of heat enhances nerve growth.  
     
     
         51 . The method of  claim 50  further comprising providing a template in an area where nerve growth is desired, wherein the template provides a pathway along which nerve growth is desired.  
     
     
         52 . The method of  claim 48  further comprising providing a template in an area where nerve growth is desired, wherein the template provides a pathway along which nerve growth is desired.  
     
     
         53 . A pharmaceutical composition, comprising: 
 a bastadin or an analog thereof; and    a pharmaceutically acceptable carrier.    
     
     
         54 . The pharmaceutical composition of  claim 53 , wherein the bastadin or analog thereof is a bastadin.  
     
     
         55 . The pharmaceutical composition of  claim 53 , wherein the bastadin or analog thereof is a bastadin or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X, Y, and Z are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         56 . The pharmaceutical composition of  claim 53  wherein the bastadin or analog therof is a bastadin or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X, Y, and Z are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         57 . The pharmaceutical composition of  claim 53  wherein the bastadin or analog thereof is a bastadin or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X, Y, and Z are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         58 . The pharmaceutical composition of  claim 53 , wherein the bastadin or analog thereof is a bastadin or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X and Y are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         59 . The pharmaceutical composition of  claim 53 , wherein the bastadin or analog thereof is a bastadin subunit or an analog thereof.  
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein the bastadin subunit or analog thereof is a bromotyrosine or an analog thereof or a bromotyrosine dimer or an analog thereof.  
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein the bastadin subunit is a bromotryosine dimer or an analog thereof.  
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein the bromotyrosine dimer or analog thereof is a hemibastadin or an analog thereof.  
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein the hemibastadin or analog thereof is a hemibastadin or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X and Y are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         64 . The pharmaceutical composition of  claim 61 , wherein the bromotyrosine dimer or analog thereof is a hemibastadinol or an analog thereof.  
     
     
         65 . The pharmaceutical composition of  claim 64 , wherein the hemibastadinol or analog thereof is a hemibastidinaol or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X and Y are selected independently from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         66 . The pharmaceutical composition of  claim 60 , wherein the bastadin subunit or an analog thereof is a bromotryosine or an analog thereof.  
     
     
         67 . The pharmaceutical composition of  claim 66 , wherein the bromotryorsine or analog thereof is a bromotyrosine or its analog having the structure:  
       
         
           
           
               
               
           
         
       
       wherein each R is independently selected from the group consisting of H, C1-8 alkyl, or sulfato, W is selected from the group consisting of H, OH, or C1-8 alkoxy, X is selected from the group consisting of hydrogen, halogen, hydroxyl, or C1-8 alkoxy, and A and B are carbon atoms that are joined by a single or a double bond.  
     
     
         68 . The pharmaceutical composition of  claim 53  further comprising a second neutrotrophic agent other than the bastadin or an analog thereof.  
     
     
         69 . The pharmaceutical composition of  claim 68 , wherein the second neurotrophoic agent is NGF, IGF-1, α-FGF, β-FGF, PDGF, BDNF, CNTF, GDNF, NT-3, NT4/5, or a mixture thereof.  
     
     
         70 . A template that provides a pathway along which nerve growth is desired that is impregnated with the pharmaceutical composition of  claim 53.