Methods of treating neurological disorders

Abstract

The present invention provides methods of treating epilepsy and other neurological disorders. The methods generally involve administering to an individual in need thereof an effective amount of an agent that blocks a transforming growth factor-beta pathway

What is claimed is: 
     
         1 . A method of treating a neurological disorder in an individual, the method comprising administering to the individual an effective amount of a transforming growth factor-beta (TGF-β) pathway blocker. 
     
     
         2 . The method of  claim 1 , wherein the TGF-β pathway blocker specifically inhibits kinase activity of TGF-β1. 
     
     
         3 . The method of  claim 1 , wherein the TGF-β pathway blocker is an aldosterone inhibitor. 
     
     
         4 . The method of  claim 3 , wherein the aldosterone inhibitor is 7α, 11α, 17α)-pregn-4-ene-7,21-dicarboxylic acid,9,11-epoxy-17-hydroxy-3-oxo-γ-lactone, methyl ester or 7α-acetylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone. 
     
     
         5 . The method of  claim 1 , wherein the TGF-β pathway blocker is an angiotensin II receptor inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the angiotensin II receptor inhibitor is 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol, N-[p-(o-1H-tetrazol-5-yl-phenyl)benzyl]-N-valeryl-L-valine, 2-n-butyl-4-spirocyclopentane-1-((2′-tetrazol-5-yl)biphenyl-4-yl)-2-imidazolin-5-one, 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, 4′-[(1,4′-dimethyl-2′-propyl[2,6-bi-1H-benzimidazol]-1-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid, 5,8-dihydro-2,4-dimethyl-8-[p-(o-1H-tetrazol-5-ylphenyl]pyrido[2,3-d]pyrimidin-7(6H)-one, or 4-((2-butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl)eth-1-en-1-yl]-1H-imidazol-1-yl)methyl)benzoic acid, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         7 . The method of  claim 5 , wherein the angiotensin II receptor inhibitor is 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 1 , wherein the TGF-β pathway blocker is an angiotensin converting enzyme (ACE) inhibitor. 
     
     
         9 . The method of  claim 1 , wherein the TGF-β pathway blocker is a renin inhibitor. 
     
     
         10 . The method of  claim 1 , wherein the TGF-β pathway blocker is a proteoglycan selected from decorin, biglycan, fibromodulin, lumican, betaglycan and endoglin. 
     
     
         11 . The method of  claim 1 , wherein the TGF-β pathway blocker is an agent that reduces the level and/or activity of Smad1. 
     
     
         12 . The method of  claim 11 , wherein the agent that reduces the level and/or activity of Smad1 is 3-(6-Methylpyridin-2-yl)-1-phenylthiocarbamoyl-4-quinolin-4-ylpyrazole, 2-phenyl-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyridine, or 4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide. 
     
     
         13 . The method of  claim 1 , wherein the TGF-β pathway blocker reduces the level and/or activity of NFκB. 
     
     
         14 . The method of  claim 1 , wherein the TGF-β pathway blocker is a mitogen activated protein kinase inhibitor. 
     
     
         15 . The method of  claim 1 , wherein the TGF-β pathway blocker is an inhibitory nucleic acid that reduces the level of a TGF-β pathway element. 
     
     
         16 . The method of  claim 1 , wherein the neurological disorder is epilepsy. 
     
     
         17 . The method of  claim 1 , wherein the neurological disorder is stroke. 
     
     
         18 . The method of  claim 1 , wherein the neurological disorder results from traumatic head injury. 
     
     
         19 . The method of  claim 1 , wherein the neurological disorder is a neurodegenerative disorder. 
     
     
         20 . The method of  claim 1 , wherein a single TGF-β pathway blocker is administered in monotherapy. 
     
     
         21 . The method of  claim 1 , wherein a single TGF-β pathway blocker is administered in combination therapy with at least one additional therapeutic agent other than a TGF-β pathway blocker. 
     
     
         22 . The method of  claim 1 , wherein the TGF-β pathway blocker is administered via injection. 
     
     
         23 . The method of  claim 1 , wherein the TGF-β pathway blocker is administered orally. 
     
     
         24 . The method of  claim 1 , wherein the TGF-β pathway blocker is administered intracranially. 
     
     
         25 . The method of  claim 1 , wherein the TGF-β pathway blocker is administered together with an agent that facilitates crossing the blood-brain barrier.