Treatment of ischemic episodes and cerebroprotection through Prostaglandin E2 (PGE2) EP2 and/or EP4 receptor agonists

Abstract

The present invention provides compositions and methods for treating an ischemic episode using PGE 2 EP 2 agonists and/or PGE 2 EP 4 agonists alone or in combination with anti-thrombotic agents.

1 . A method of treating an ischemic episode in a subject, the method comprising administering to said subject a therapeutically effective amount of a therapeutic agent selected from the group consisting of PGE 2  EP 2  agonists, PGE 2  EP 4  agonists, mixed PGE 2  EP 2 /EP 4  agonists, and mixtures or metabolic precursors thereof. 
     
     
         2 . The method of  claim 1 , wherein the ischemic episode is caused by stroke or cardiac arrest. 
     
     
         3 . The method of  claim 1 , wherein the therapeutic agent is misoprostol or an analog of misoprostol. 
     
     
         4 . The method of  claim 1 , wherein the therapeutic agent is ONO-AE1-329 or an analog of ONO-AE1-329. 
     
     
         5 . A method of treating or preventing a neurological disorder resulting from exposure of neurons to ischemia in a subject, the method comprising administering to said subject a therapeutically effective amount of a therapeutic agent selected from the group consisting of PGE 2  EP 2  agonists, PGE 2  EP 4  agonists, mixed PGE 2  EP 2 /EP 4  agonists, and mixtures or metabolic precursors thereof. 
     
     
         6 . The method of  claim 5 , wherein said ischemia is caused by stroke or cardiac arrest. 
     
     
         7 . The method of  claim 5 , wherein the therapeutic agent is misoprostol or an analog of misoprostol. 
     
     
         8 . The method of  claim 5 , wherein the therapeutic agent is ONO-AE1-329 or an analog of ONO-AE1-329. 
     
     
         9 . A method of screening a candidate compound for efficacy in treating an ischemic episode, the method comprising
 (a) assaying said compound for activation of the PGE 2  EP 2  and/or PGE 2  EP 4  receptor to determine an PGE 2  EP 2  agonist, PGE 2  EP 4  agonist or mixed PGE 2  EP 2 /EP 4  agonist;   (b) contacting a model for said ischemic episode with said PGE 2  EP 2  agonist, PGE 2  EP 4  agonist or mixed PGE 2  EP 2 /EP 4  agonist; and   (c) determining the efficacy of said PGE 2  EP 2  agonist, PGE 2  EP 4  agonist or mixed PGE 2  EP 2 /EP 4  agonist in treating said ischemic episode.   
     
     
         10 . A pharmaceutical composition comprising (a) a therapeutic agent selected from the group consisting of PGE 2  EP 2  agonists, PGE 2  EP 4  agonists, mixed PGE 2  EP 2 /EP 4  agonists, and mixtures, metabolic precursors or pharmaceutically acceptable derivatives thereof; and (b) an anti-thrombotic agent or a pharmaceutically acceptable derivative thereof; in a mixture with a pharmaceutically acceptable carrier. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein (a) the therapeutic agent is misoprostol or an analog of misoprostol and (b) the anti-thrombotic agent is tissue plasminogen activator. 
     
     
         12 . The pharmaceutical composition according to  claim 10 , wherein (a) the therapeutic agent is ONO-AE1-329 or an analog of ONO-AE1-329 and (b) the anti-thrombotic agent is tissue plasminogen activator. 
     
     
         13 . A method of treating an ischemic episode in a subject, the method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to  claim 10 ,  11  or  12 . 
     
     
         14 . A method of treating or preventing a neurological disorder resulting from exposure of neurons to ischemia in a subject, the method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to  claim 10 ,  11  or  12 .