Compositions and methods for treating refractory seizures

Abstract

The present invention relates to the field of seizures. More specifically, the present invention provides compositions and methods for treating refractory seizures in neonates. In one embodiment, the method comprises the steps of (a) administering to the patient an amount of a KCC2 agonist and/or trkB antagonist effective to restore KCC2 expression to normal physiological levels; and (b) administering to the patient an effective amount of an anti-seizure medication.

1 . A method for treating refractory seizures in a neonatal patient comprising the steps of:
 a. administering to the patient an amount of a KCC2 agonist and/or trkB antagonist effective to restore KCC2 expression to normal physiological levels; and   b. administering to the patient an effective amount of an anti-seizure medication.   
     
     
         2 . The method of  claim 1 , wherein the seizure is an ischemia-related seizure. 
     
     
         3 . The method of  claim 1 , wherein the KCC2 agonist comprises N-ethylmaleimide (NEM), the chloride channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), CLP257, or CLP290. 
     
     
         4 . The method of  claim 1 , wherein the trkB antagonist comprises ANA-12, N-T19, K252a or cyclotraxin-B. 
     
     
         5 . The method of  claim 1 , wherein the KCC2 agonist is CLP290. 
     
     
         6 . The method of  claim 1 , wherein the trkB antagonist is ANA-12. 
     
     
         7 . The method of  claim 1 , wherein the anti-seizure medication is phenobarbital or phenytoin. 
     
     
         8 . A method for treating refractory seizures in a neonatal patient comprising the steps of:
 a. administering to the patient an amount of ANA-12 and/or CLP290 effective to restore KCC2 expression to normal physiological levels; and   b. administering to the patient an effective amount of an anti-seizure medication.   
     
     
         9 . The method of  claim 8 , wherein the seizure is an ischemia-related seizure. 
     
     
         10 . The method of  claim 8 , wherein the anti-seizure medication is phenobarbital or phenytoin. 
     
     
         11 . A method for treating refractory seizures in a neonatal patient comprising the steps of:
 a. administering to the patient an amount of ANA-12 and/or CLP290 effective to restore KCC2 expression to normal physiological levels; and   b. administering to the patient an effective amount of phenobarbital.   
     
     
         12 . A method for treating refractory seizures in a patient comprising the steps of:
 a. administering to the patient an effective amount of an agent that increases KCC2 expression back to normal levels, wherein the seizure downregulates KCC2 expression; and   b. administering to the patient an effective amount of an anti-seizure medication.   
     
     
         13 . The method of  claim 12 , wherein the patient is a neonate. 
     
     
         14 . The method of  claim 13 , wherein the neonate is administered a transient dose of an anti-seizure medication. 
     
     
         15 . A method for treating ischemia-related seizures in a neonatal patient comprising the steps of:
 a. administering a KCC2 agonist and/or a trkB antagonist in an amount(s) effective to restore KCC2 expression back to normal physiological levels; and   b. administering a transient dose of an anti-seizure medication in an amount effective to stop the seizures.   
     
     
         16 - 19 . (canceled) 
     
     
         20 . The method of  claim 5 , wherein the effective amount of the anti-seizure medication or phenobarbital is reduced due to anti-seizure activity of CLP290.