Novel non-selective cation channel in neuronal cells and method for treating brain swelling

Abstract

The present invention is directed to therapeutic compounds, treatment methods, and kits affecting the NC Ca-ATP channel of neural tissue, including neurons, glia and blood vessels within the nervous system, and methods of using same. The NC Ca-ATP channel is newly expressed in neural tissue following injury such as ischemia, and is regulated by the sulfonylurea receptor SUR1, being inhibited by sulfonylurea compounds, e.g., glibenclamide and tolbutamide, and opened by diazoxide. Antagonists of the NC Ca-ATP channel, including SUR1 antagonists, are useful in the prevention, diminution, and treatment of injured or diseased neural tissue, including astrocytes, neurons and capillary endothelial cells, that is due to ischemia, tissue trauma, brain swelling and increased tissue pressure, or other forms of brain or spinal cord disease or injury. Agonists of the NC Ca-ATP channel may be are useful in the treatment neural tissue where damage or destruction of the tissue, such as a gliotic capsule, is desired.

1 - 35 . (canceled) 
     
     
         36 . Method of prophylaxis, therapy and/or diagnosis of a subject suffering from or susceptible to CNS acute damage, said method comprising: administering to the subject an effective amount of a K ATP  channel closer (KCC), or of an isotopically modified species thereof, together with appropriate amounts of acceptable diluents or carriers. 
     
     
         37 . The method according to  claim 36 , wherein the K ATP  channel closer is a sulfonylurea. 
     
     
         38 . The method according to  claim 37 , wherein the damage is caused by a CNS injury. 
     
     
         39 . The method according to  claim 38 , wherein the CNS injury is selected from the group consisting of brain injury, spinal cord injury, global ischemia, focal ischemia, hypoxia, stroke, seizure, epilepsy, status epilepticus, CNS vascular disease, neuroocular disease and trauma. 
     
     
         40 . The method according to  claim 37 , wherein the damage is caused by a CNS degenerative disease. 
     
     
         41 . The method according to  claim 40 , wherein the CNS degenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, encephalopathy and adrenoleukodystrophy. 
     
     
         42 . The method according to  claim 37 , wherein the damage is caused by a CNS infectious disease. 
     
     
         43 . The method according to  claim 42 , wherein the CNS infectious disease is selected from the group consisting of viral infection, parasitic infection, bacterial infection, mycoplasma infection and fungal infection. 
     
     
         44 . The method according to  claim 37 , wherein the damage is caused by an autoimmune disease. 
     
     
         45 . The method according to  claim 44 , wherein the autoimmune disease is selected from the group consisting of multiple sclerosis and phenylketonuria. 
     
     
         46 . The method according to  claim 37 , wherein the damage is caused by a nutritional, metabolic or toxic disorder. 
     
     
         47 . The method according to  claim 46 , wherein the disorder is selected from the group consisting of hepatic encephalopathy, lead poisoning and stupefying drug poisoning. 
     
     
         48 . The method according to  claim 36 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         49 . The method according to  claim 37 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         50 . The method according to  claim 38 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         51 . The method according to  claim 39 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         52 . The method according to  claim 40 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         53 . The method according to  claim 41 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         54 . The method according to  claim 42 , wherein the K ATP  channel closer is glibenclamide. 
     
     
         55 . A method of treating brain damage in a subject comprising contacting said subject with a sulfonylurea. 
     
     
         56 . The method of  claim 55 , wherein brain damage comprises cerebral ischemia, traumatic brain damage, and cytotoxic swelling. 
     
     
         57 . The method of  claim 55 , wherein brain damage comprises stroke. 
     
     
         58 . A method of treating neural cell swelling in a subject comprising contacting said subject with a sulfonylurea. 
     
     
         59 . The method of  claim 57 , wherein said neural cell is an astrocyte. 
     
     
         60 . A method of treating central nervous system damage in a subject comprising contacting said subject with a sulfonylurea. 
     
     
         61 . The method of  claim 59 , wherein said central nervous system damage comprises brain injury, spinal cord injury, global ischemia, focal ischemia, hypoxia, or stroke.