Novel non-selective cation channel in neuronal cells and methods 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.

What is claimed is: 
     
         1 . A method of ameliorating the effect of a reduction in blood flow in peri-infarct brain tissue in ischemic disease or injury in a subject comprising administering to the subject an amount of a compound effective to inhibit the activity of a NC Ca-ATP  channel in a neuronal cell, a neuroglia cell, or a neural endothelial cell. 
     
     
         2 . The method of  claim 1 , where said compound is a compound capable of effecting hypoglycemia in said subject, further comprising administration of glucose to said subject effective to at least partially ameliorate said hypoglycemic effects in said subject. 
     
     
         3 . A method of inhibiting neuronal cell swelling in the brain of a subject, said method comprising administering to the subject a formulation comprising an effective amount of a compound that blocks the NC Ca-ATP  channel and a pharmaceutically acceptable carrier. 
     
     
         4 . The method of  claim 3 , wherein said inhibiting neuronal cell swelling is further defined as preventing neuronal cell swelling. 
     
     
         5 . The method of  claim 3 , where said formulation comprises a compound capable of effecting hypoglycemia in said subject, further comprising administration of glucose to said subject effective to at least partially ameliorate said hypoglycemic effects in said subject. 
     
     
         6 . The method of  claim 5 , wherein said inhibiting neuronal cell swelling is further defined as preventing neuronal cell swelling. 
     
     
         7 . The method of  claim 1 , wherein the amelioration of the effect of a reduction in blood flow comprises a reduction in cytotoxic edema, ionic edema and/or vasogenic edema. 
     
     
         8 . The method of  claim 1 , wherein the neuroglia cell is selected from the group consisting of astrocyte, ependymal cell, oligodentrocyte and microglia. 
     
     
         9 . The method of  claim 1 , wherein the NC Ca-ATP  channel inhibitor is a type 1 sulfonylurea receptor antagonist selected from the group consisting of glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, zearalenone, a compound that inhibits K ATP  channels. 
     
     
         10 . A method of alleviating brain swelling in a subject, comprising administering to the subject a formulation comprising an effective amount of a compound that blocks the NC Ca-ATP  channel and a pharmaceutically acceptable carrier. 
     
     
         11 . The method of  claim 10 , where said formulation is a formulation capable of effecting hypoglycemia in said subject, further comprising administration of glucose to said subject effective to at least partially ameliorate said hypoglycemic effects in said subject. 
     
     
         12 . The method of  claim 1 , wherein compound effective to inhibit a NC Ca-ATP  channel is administered alimentarily, parenterally, topically, mucosally, or by injection into brain parenchema. 
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of a compound that inhibits a NC Ca-ATP  channel or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is effective to ameliorate at least one effect of a reduction in blood flow in peri-infarct brain tissue in a subject suffering from ischemic disease in the brain or from brain injury. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the compound that inhibits a NC Ca-ATP  channel is selected from the group consisting of glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, and zearalenone. 
     
     
         15 . The pharmaceutical composition of  claim 13  wherein the composition further comprises glucose. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the amount of said compound that inhibits a NC Ca-ATP  channel or pharmaceutically acceptable salt thereof is an amount that has a hypoglycemic effect in a subject to which the pharmaceutical composition is administered. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the amount of said glucose is effective to reduce or eliminate a lowering of the blood glucose concentration by said compound or pharmaceutically acceptable salt in the subject to which the pharmaceutical composition is administered. 
     
     
         18 . The pharmaceutical composition of  claim 13 , wherein the pharmaceutical composition is neuroprotective. 
     
     
         19 . The pharmaceutical composition of  claim 15 , wherein the pharmaceutical composition is neuroprotective. 
     
     
         20 . A method of treating acute cerebral ischemia in a subject comprising administering to a subject an amount of a compound that inhibits a NC Ca-ATP  channel or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 20 , wherein the NC Ca-ATP  channel is expressed on neuronal cells, neuroglia cells, neural endothelial cells or a combination thereof. 
     
     
         22 . The method of  claim 20 , wherein said NC Ca-ATP  channel inhibitor is selected from the group consisting of glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, and zearalenone. 
     
     
         23 . The method of  claim 20 , wherein the mode of administration of said NC Ca-ATP  channel inhibitor is selected from the group of modes of administration consisting of bolus injection, infusion, and bolus injection in combination with an infusion. 
     
     
         24 . The method of  claim 20 , wherein said NC Ca-ATP  channel inhibitor is glibenclamide. 
     
     
         25 . The method of  claim 20 , further comprising administering glucose to said subject. 
     
     
         26 . The method of  claim 25 , wherein said NC Ca-ATP  channel inhibitor is selected from the group consisting of glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, midaglizole, LY397364, LY389382, glyclazide, glimepiride, estrogen, estradiol, estrone, estriol, genistein, diethystilbestrol, coumestrol, and zearalenone. 
     
     
         27 . The method of  claim 26 , wherein the mode of administration of said NC Ca-ATP  channel inhibitor is selected from the group of modes of administration consisting of bolus injection, infusion, and bolus injection in combination with an infusion. 
     
     
         28 . The method of  claim 20 , wherein compound effective to inhibit a NC Ca-ATP  channel is administered alimentarily, parenterally, topically, mucosally, or by injection into brain parenchema. 
     
     
         29 . A neuroprotective infusion kit comprising a compound that inhibits a NC Ca-ATP  channel in a neuronal cell, a neuroglia cell, a neural endothelial cell or a combination thereof and an intravenous (IV) infusion solution. 
     
     
         30 . The neuroprotective infusion kit of  claim 29 , wherein said IV infusion solution is an IV infusion solution supplemented with glucose. 
     
     
         31 . The neuroprotective infusion kit of  claim 29  further comprising a neuroprotective bolus kit, wherein the neuroprotective bolus kit comprises a pre-loaded syringe of a compound that inhibits a NC Ca-ATP  channel in a neuronal cell, a neuroglia cell, a neural endothelial cell or a combination thereof within an IV solution. 
     
     
         32 . The kit of  claim 31 , wherein said IV solution is an IV solution supplemented with glucose. 
     
     
         33 . A method of preventing neural cell swelling in the brain of a subject, said method comprising administering to the subject a formulation comprising an effective amount of a compound that blocks the NC Ca-ATP  channel, glucose, and a pharmaceutically acceptable carrier. 
     
     
         34 . A method of alleviating one or more effects of traumatic brain injury or cerebral ischemia stemming from neural cell swelling in a subject, comprising administering to the subject a formulation comprising an effective amount of a compound that blocks the NC Ca-ATP  channel, glucose, and a pharmaceutically acceptable carrier. 
     
     
         35 . A method of alleviating one or more effects of traumatic brain injury or cerebral ischemia in a subject, comprising administering to the subject a formulation comprising an effective amount of a sulfonylurea compound and a pharmaceutically acceptable carrier.