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 an adult 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 an adult 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.