Sigma ligands for neuronal regeneration and functional recovery

Abstract

The invention discloses methods and compositions useful for facilitating neuronal regeneration and functional recovery in neurodegenerative diseases. The methods and compositions utilize ligands for the sigma receptor, wherein the ligand is preferably AGY-94806, or salts, or solvates thereof. These molecules can be delivered alone or in combination with agents which treat or prevent neurodegenerative diseases such as those caused by multiple sclerosis. In other methods, the sigma receptor ligands are administered after MS to facilitate functional recovery. The administration of the sigma receptor ligands causes fasted functional recovery.

1 . A method of treating a mammalian subject to facilitate neuronal regeneration after onset of multiple sclerosis (MS), the method comprising administering to the subject a pharmaceutically effective amount of AGY-94806, or salts or solvates thereof. 
     
     
         2 . A method for treating a demyelinating disorder, comprising administering to a subject having developed signs of the disorder the sigma receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (AGY-94806, also known as SA-4503), or a pharmaceutically acceptable salt thereof, in an amount effective to provide a reduction of pathological damage associated with the disorder. 
     
     
         3 . The method of  claim 2 , wherein the subject is a human. 
     
     
         4 . The method of  claim 3 , wherein the pathological damage includes one or more of i) inflammatory lesions, ii) demyelinating lesions, and iii) axonal damage or loss. 
     
     
         5 . The method of  claim 4 , wherein the reduction of pathological damage is evidenced by a reduction of inflammatory lesions. 
     
     
         6 . The method of  claim 4 , wherein the reduction of pathological damage is evidenced by a reduction of demyelinating lesions. 
     
     
         7 . The method of  claim 4 , wherein the reduction of pathological damage is evidenced by a reduction of axonal damage or loss. 
     
     
         8 . The method of  claim 4 , wherein the reduction of pathological damage is evidenced by enhanced recovery of neurological score. 
     
     
         9 . The method of  claim 4 , wherein the reduction of pathological damage is evidenced by imaging. 
     
     
         10 . The method of  claim 9 , wherein the imaging is magnetic resonance imaging. 
     
     
         11 . A method for treating a demyelinating disorder, comprising administering to a human subject who has developed signs of the disorder the sigma receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (AGY-94806, also known as SA-4503), or a pharmaceutically acceptable salt thereof, further comprising administering SA-4503 in a dosage up to 0.50 mg/kg. 
     
     
         12 . The method of  claim 11 , wherein SA-4503 is administered in a dosage of about 0.05 mg/kg. 
     
     
         13 . The method of  claim 11 , wherein the reduction of pathological damage is evidenced by a reduction of one or more of i) inflammatory lesions, ii) demyelinating lesions, and iii) axonal damage or loss. 
     
     
         14 . A method for treating a demyelinating disorder, comprising administering to a human subject who has developed signs of the disorder the sigma receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (AGY-94806, also known as SA-4503), or a pharmaceutically acceptable salt thereof, further comprising administering SA-4503 daily. 
     
     
         15 . The method of  claim 14 , wherein SA-4503 is administered until a desired reduction of pathological damage is attained. 
     
     
         16 . The method of  claim 14 , wherein the reduction of pathological damage is evidenced by a reduction of one or more of i) inflammatory lesions, ii) demyelinating lesions, and iii) axonal damage or loss. 
     
     
         17 . A method for treating a demyelinating disorder, comprising administering to a human subject who has developed signs of the disorder the sigma receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (AGY-94806, also known as SA-4503), or a pharmaceutically acceptable salt thereof, further comprising administering SA-4503 in a total daily dosage of about 3.5 mg until a desired reduction of pathological damage is attained. 
     
     
         18 . The method of  claim 17 , wherein the total daily dosage is about 3 mg until a desired reduction of pathological damage is attained. 
     
     
         19 . The method of  claim 17  or  claim 18 , wherein the reduction of pathological damage is evidenced by a reduction of one or more of i) inflammatory lesions, ii) demyelinating lesions, and iii) axonal damage or loss. 
     
     
         20 . A method for treating multiple sclerosis, comprising administering to a human subject having developed signs of multiple sclerosis the sigma receptor ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (AGY-94806, also known as SA-4503), or a pharmaceutically acceptable salt thereof, in an amount effective to provide a reduction of pathological damage associated with multiple sclerosis. 
     
     
         21 . The method of  claim 20 , wherein the reduction of pathological damage is evidenced by a reduction of one or more of i) inflammatory lesions, ii) demyelinating lesions, and iii) axonal damage or loss. 
     
     
         22 . The method of  claim 21 , further comprising administering SA-4503 in a dosage up to 0.5 mg/kg. 
     
     
         23 . The method of  claim 22 , wherein SA-4503 is administered in a dosage of about 0.05 mg/kg. 
     
     
         24 . The method of  claim 20 , wherein SA-4503 is administered daily. 
     
     
         25 . The method of  claim 20 , wherein SA-4503 is administered until a desired reduction of pathological damage is attained.