Inhibitor of trpm-4 ion channel for treating or preventing neurodegeneration

Abstract

The invention relates to a compound which is effective in inhibiting the function of the TRPM4 ion channel and the use of such compound in treating or preventing a neurodegenerative disease, such as Multiple Sclerosis, Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis, in a subject. The invention also provides a pharmaceutical composition comprising a TRPM4 inhibitory compound. The invention further relates to in vitro methods for identifying pharmaceutically active compounds that are useful for treating or preventing a neurodegenerative disease.

1 . A method of treating Multiple Sclerosis in a subject, comprising administering to a subject that suffers from Multiple Sclerosis a therapeutically effective amount of a compound which is effective in inhibiting the function of a TRPM4 ion channel and inhibits or reduces axonal injury in the subject. 
     
     
         2 . The method according to  claim 1 , wherein the compound is selected from the group consisting of glibenclamide, 9-phenanthrol, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, non-steroidal estrogen, phytoestrogen, zearalenone, 5-butyl-7-chloro-6-hydroxybenzo[c]-quinolizium chloride, flufenamic acid, and spermine. 
     
     
         3 . The method according to  claim 1 , wherein the compound is to be administered in an amount from 1.0 μg/kg body weight to 5,000 μg/kg body weight. 
     
     
         4 . The method according to  claim 1 , wherein the compound is administered in an amount from 100 μg/kg body weight to 800 μg/kg body weight. 
     
     
         5 . The method according to  claim 1 , wherein the compound is administered in an amount from 300 μg/kg body weight to 600 μg/kg body weight. 
     
     
         6 . The method according to  claim 1 , wherein the compound is administered orally, via intravenous injection, or via intravenous infusion. 
     
     
         7 . A method of treating Multiple Sclerosis in a subject, comprising administering to a subject that suffers from Multiple Sclerosis a pharmaceutical composition comprising a therapeutically effective amount of a compound which is effective in inhibiting the function of a TRPM4 ion channel and inhibits or reduces axonal injury in the subject. 
     
     
         8 . The method according to  claim 7 , which further comprises at least one excipient, diluent, carrier and/or at least one additional pharmaceutically active compound which is useful in the treatment of Multiple Sclerosis. 
     
     
         9 . The method according to  claim 7 , wherein the compound is selected from the group consisting of glibenclamide, 9-phenanthrol, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, non-steroidal estrogen, phytoestrogen, zearalenone, 5-butyl-7-chloro-6-hydroxybenzo[c]-quinolizium chloride, flufenamic acid, and spermine. 
     
     
         10 . The method according to  claim 7 , further comprising administering one or more other anti-neurodegenerative or anti-inflammatory compounds selected from the group consisting of interferon beta-1a, interferon beta-1b, fampridine, fingolimod hydrochloride, natalizumab, glatiramer acetate, and mitoxantrone. 
     
     
         11 . The method according to  claim 10 , wherein said other anti-neurodegenerative or anti-inflammatory compound is administered in a pharmaceutical composition that is separate from said pharmaceutical composition comprising said compound which is effective in inhibiting the function of a TRPM4 ion. 
     
     
         12 . The method according to  claim 10 , wherein said other anti-neurodegenerative or anti-inflammatory compound and said compound which is effective in inhibiting the function of a TRPM4 ion are administered according to a weekly dosing regimen. 
     
     
         13 . In vitro method for identifying a pharmaceutically active compound for treating or preventing a neurodegenerative disease in a subject, comprising:
 (a) contacting a candidate compound with a functional TRPM4 ion channel; and   (b) detecting whether said candidate compound interferes with a function of the TRPM4 ion channel or decreases transcription of the TRPM4 gene and/or the translation of the TRPM4 mRNA;   wherein a compound which inhibits the function of the TRPM4 ion channel or decreases the transcription of the TRPM4 gene and/or the translation of the TRPM4 mRNA is suitable for treating or preventing said neurodegenerative disease.   
     
     
         14 . The method of  claim 13 , wherein said neurodegenerative disease is associated with glutamate excitotoxicity. 
     
     
         15 . The method of  claim 13 , wherein said neurodegenerative disease is Multiple Sclerosis. 
     
     
         16 . A polypeptide comprising the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2 or a variant thereof having at least 80% sequence identity to the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2; or a polynucleotide encoding a polypeptide comprising the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2 or a variant thereof having at least 80% sequence identity to the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:2, or the complement thereof for identifying a pharmaceutically active compound for treating or preventing a neurodegenerative disease. 
     
     
         17 . The polypeptide or polynucleotide of  claim 16 , wherein said neurodegenerative disease is Multiple Sclerosis.