Promoters of neural regeneration

Abstract

The invention provides methods and compositions for promoting neural cell growth and/or regeneration. The general methods involve contacting with an activator of a cyclic nucleotide dependent protein kinase a neural cell subject to growth repulsion mediated by a neural cell growth repulsion factor. The activator may comprise a direct or an indirect activator of the protein kinase; the repulsion factor typically comprises one or more natural, endogenous proteins mediating localized repulsion or inhibition of neural cell growth; and the target cells are generally vertebrate neurons, typically injured mammalian neurons. The subject compositions include mixtures comprising a neural cell, an activator of a cyclic nucleotide dependent protein kinase and a neural cell growth repulsion factor.

What is claimed is:  
     
         1 . A method for promoting growth of a human central nervous system neuron damaged by a spinal injury and subject to growth inhibition by an endogenous neural cell growth repulsion factor, the method comprising the steps of locally administering to a human patient in need thereof at an axon of the neuron a therapeutically effective amount of an activator of a cyclic nucleotide dependent protein kinase, whereby growth of the axon is promoted; and detecting a resultant growth promotion of the axon.  
     
     
         2 . The method of  claim 1 , wherein the activator comprises an active component selected from a cyclic nucleotide analog, an activator of a cyclic nucleotide cyclase, a nitric oxide (NO) inducer and an inhibitor of a cyclic nucleotide phosphodiesterase.  
     
     
         3 . The method of  claim 1 , wherein the activator comprises an active component selected from: 
 (a) an activator of a cyclic nucleotide cyclase selected from an adenylate cyclase activator selected from forskolin, 7β-deaceyl-7β-[γ-(morpholino)butyryl]-forskolin and 6β-[β′-(piperidino)-propionyl]-forskolin; and a guanylate cyclase activator which is protoporphyrin-9 (PP-9);    (b) a cyclic nucleotide analog selected from a protein kinase-A (PKA) activator selected from 8-bromo-adenosine 3′, 5′-monophosphate (8-Br-cAMP), 8-chloro-adenosine 3′, 5′-monophosphate (8-Cl-cAMP), 8-(4-chlorophenylthio)-cAMP, dibutyryl-cAMP, dioctanoyl-cAMP, Sp-cAMPS and Sp-8-bromo-cAMPS; and a protein kinase G (PKG) activator selected from 8-br-cGMP, 8-(4-chlorophenylthio)-cGMP and dibutyryl-cGMP;    (c) a NO inducer which is an NO donor selected from S-nitroso-N-acetylpenicillamine (SNAP), Glyco-SNAP-1, Glyco-SNAP-2, 2,2′-(hydroxynitrosohydrazono)bis-ethanamine (NOC-18) and (+/−)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3); and    (d) an inhibitor of a cyclic nucleotide phosphodiesterase selected from 3-isobutyl-1-methylxanthine (IBMX) and rolipram.    
     
     
         4 . The method of  claim 1 , wherein the activator comprises an active component that is forskolin.  
     
     
         5 . The method of  claim 1 , wherein the activator comprises an active component that is 7β-deaceyl- 7β-[γ-(morpholino)butyryl]-forskolin.    
     
     
         6 . The method of  claim 1 , wherein the activator comprises an active component that is 6β-[β′-(piperidino)-propionyl]-forskolin.  
     
     
         7 . The method of  claim 1 , wherein the activator comprises an active component that is protoporphyrin-9 (PP-9).  
     
     
         8 . The method of  claim 1 , wherein the activator comprises an active component that is 8-bromo-adenosine 3′, 5′-monophosphate (8-Br-cAMP).  
     
     
         9 . The method of  claim 1 , wherein the activator comprises an active component that is 8-chloro-adenosine 3′, 5′-monophosphate (8-Cl-cAMP).  
     
     
         10 . The method of  claim 1 , wherein the activator comprises an active component that is 8-(4-chlorophenylthio)-cAMP).  
     
     
         11 . The method of  claim 1 , wherein the activator comprises an active component that is dibutyryl-cAMP.  
     
     
         12 . The method of  claim 1 , wherein the activator comprises an active component that is dioctanoyl-cAMP.  
     
     
         13 . The method of  claim 1 , wherein the activator comprises an active component that is Sp-cAMPS.  
     
     
         14 . The method of  claim 1 , wherein the activator comprises an active component that is Sp-8-bromo-cAMPS.  
     
     
         15 . The method of  claim 1 , wherein the activator comprises an active component that is 8-br-cGMP.  
     
     
         16 . The method of  claim 1 , wherein the activator comprises an active component that is 8-(4-chlorophenylthio)-cGMP.  
     
     
         17 . The method of  claim 1 , wherein the activator comprises an active component that is dibutyryl-cGMP.  
     
     
         18 . The method of  claim 1 , wherein the activator comprises an active component that is S-nitroso-N-acetylpenicillamine (SNAP).  
     
     
         19 . The method of  claim 1 , wherein the activator comprises an active component that is Glyco-SNAP-1.  
     
     
         20 . The method of  claim 1 , wherein the activator comprises an active component that is Glyco-SNAP-2.  
     
     
         21 . The method of  claim 1 , wherein the activator comprises an active component that is 2,2′-(hydroxynitrosohydrazono) bis-ethanamine (NOC-18).  
     
     
         22 . The method of  claim 1 , wherein the activator comprises an active component that is (+/−)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3).  
     
     
         23 . The method of  claim 1 , wherein the activator comprises an active component that is 3-isobutyl-1-methylxanthine (IBMX).  
     
     
         24 . The method of  claim 1 , wherein the activator comprises an active component that is rolipram.  
     
     
         25 . The method of  claim 1 , wherein the repulsion factor comprises an active component selected from a semaphorin, a netrin, a MAG and a CNS myelin fraction.  
     
     
         26 . The method of  claim 1 , wherein the protein kinase is protein kinase A or G.  
     
     
         27 . The method of  claim 1 , wherein the neuron is a corticospinal tract neuron.