Methods for modulating the axonal outgrowth of central nervous system neurons

Abstract

Methods for modulating the axonal outgrowth of central nervous system neurons are provided. Methods for stimulating the axonal outgrowth of central nervous system neurons following an injury (e.g., stroke, Traumatic Brain Injury, cerebral aneurism, spinal cord injury and the like) and methods for inhibiting the axonal outgrowth of central nervous system neurons are also provided. Finally, a packed formulation comprising a pharmaceutical composition comprising an inosine nucleoside and a pharmaceutically acceptable carrier packed with instructions for use of the pharmaceutical composition for treatment of a central nervous system disorder is provided.

We claim:  
     
         1 . A method for modulating axonal outgrowth of central nervous system neurons, the method comprising contacting the central nervous system neurons with a pharmaceutical composition consisting essentially of an effective amount of a purine nucleoside, or analog thereof, such that axonal outgrowth is modulated.  
     
     
         2 . The method of  claim 1 , wherein the outgrowth is stimulated.  
     
     
         3 . The method of  claim 2 , wherein the purine nucleoside is inosine.  
     
     
         4 . The method of  claim 2 , wherein the purine nucleoside is guanosine.  
     
     
         5 . The method of  claim 1 , wherein the outgrowth is inhibited.  
     
     
         6 . The method of  claim 5 , wherein the purine nucleoside is 6-thioguanine.  
     
     
         7 . The method of  claim 1 , wherein said central nervous system neurons are mammalian.  
     
     
         8 . A method for stimulating the axonal outgrowth of central nervous system neurons following an injury, comprising administering to a subject a purine nucleoside, or analog thereof, such that axonal outgrowth is stimulated.  
     
     
         9 . The method of  claim 8 , wherein the injury is due to a stroke episode.  
     
     
         10 . The method of  claim 8 , wherein the injury is due to a Traumatic Brain Injury (TBI) episode.  
     
     
         11 . The method of  claim 8 , wherein the injury is due to a cerebral aneurism.  
     
     
         12 . The method of  claim 8 , wherein the injury is a spinal cord injury.  
     
     
         13 . The method of  claim 12 , wherein the spinal cord injury is selected from the group consisting of monoplegia, diplegia, paraplegia, hemiplegia and quadriplegia.  
     
     
         14 . The method of  claim 8 , wherein the purine nucleoside or analog thereof is administered by introduction into the central nervous system of the subject.  
     
     
         15 . The method of  claim 14 , wherein the purine nucleoside or analog thereof is introduced into the cerebrospinal fluid of the subject.  
     
     
         16 . The method of  claim 15 , wherein the purine nucleoside or analog thereof is introduced intrathecally.  
     
     
         17 . The method of  claim 15 , wherein the purine nucleoside or analog thereof is introduced into a cerebral ventricle.  
     
     
         18 . The method of  claim 15 , wherein the purine nucleoside or analog thereof is introduced into the lumbar area.  
     
     
         19 . The method of  claim 15 , wherein the purine nucleoside or analog thereof is introduced into the cisterna magna.  
     
     
         20 . The method of  claim 8 , wherein the purine nucleoside is inosine.  
     
     
         21 . The method of  claim 8 , wherein the purine nucleoside is guanosine.  
     
     
         22 . The method of  claim 8 , wherein the subject is a mammal.  
     
     
         23 . The method of  claim 22 , wherein the mammal is a human.  
     
     
         24 . The method of  claim 8 , wherein the purine nucleoside or analog thereof is administered in a pharmaceutically acceptable formulation.  
     
     
         25 . The method of  claim 24 , wherein the pharmaceutically acceptable formulation is a dispersion system.  
     
     
         26 . The method of  claim 25 , wherein the pharmaceutically acceptable formulation comprises a lipid-based formulation.  
     
     
         27 . The method of  claim 26 , wherein the pharmaceutically acceptable formulation comprises a liposome formulation.  
     
     
         28 . The method of  claim 27 , wherein the pharmaceutically acceptable formulation comprises a multivesicular liposome formulation.  
     
     
         29 . The method of  claim 25 , wherein the pharmaceutically acceptable formulation comprises a polymeric matrix.  
     
     
         30 . The method of  claim 29 , wherein the polymeric matrix is selected from the group consisting of naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides.  
     
     
         31 . The method of  claim 29 , wherein the polymeric matrix is selected from the group consisting of synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics.  
     
     
         32 . The method of  claim 29 , wherein the polymeric matrix is in the form of microspheres.  
     
     
         33 . The method of  claim 24 , wherein the pharmaceutically acceptable formulation provides sustained delivery of the purine nucleoside to a subject for at least one week after the pharmaceutically acceptable formulation is administered to the subject.  
     
     
         34 . The method of  claim 24 , wherein the pharmaceutically acceptable formulation provides sustained delivery of the purine nucleoside to a subject for at least two weeks after the pharmaceutically acceptable formulation is administered to the subject.  
     
     
         35 . The method of  claim 24 , wherein the pharmaceutically acceptable formulation provides sustained delivery of the purine nucleoside to a subject for at least three weeks after the pharmaceutically acceptable formulation is administered to the subject.  
     
     
         36 . The method of  claim 24 , wherein the pharmaceutically acceptable formulation provides sustained delivery of the purine nucleoside to a subject for at least four weeks after the pharmaceutically acceptable formulation is administered to the subject.  
     
     
         37 . The method of  claim 20 , wherein the inosine nucleoside is administered at a concentration of 5-10 μM.  
     
     
         38 . The method of  claim 20 , wherein the inosine nucleoside is administered at a concentration of 10-25 μM.  
     
     
         39 . The method of  claim 20 , wherein the inosine nucleoside is administered at a concentration of 25-50 μM.  
     
     
         40 . The method of  claim 21 , wherein the guanosine nucleoside is administered at a concentration of 25-50 μM.  
     
     
         41 . The method of  claim 21 , wherein the guanosine nucleoside is administered at a concentration of 50-100 μM.  
     
     
         42 . The method of  claim 21 , wherein the guanosine nucleoside is administered at a concentration of 100-150 μM.  
     
     
         43 . The method of  claim 8 , wherein the central nervous system neurons are retinal ganglion cells.  
     
     
         44 . A pa  nervous system disorder.