Metabolic intervention with GLP-1 or its biologically active analogues to improve the function of the ischemic and reperfused brain

Abstract

It has now been discovered that GLP-1 treatment after acute stroke or hemorrhage, preferably intravenous administration, can be an ideal treatment because it provides a means for optimizing insulin secretion, increasing brain anabolism, enhancing insulin effectiveness by suppressing glucagon, and maintaining euglycemia or mild hypoglycemia with no risk of severe hypoglycemia.

1. A method of increasing insulinotropic response in ischemia  treating reperfusion-injured brain cells after an ischemic event comprising administering a composition containing glucagon-like peptide-1 (GLP-1) and a pharmaceutical carrier for a time sufficient and under conditions effective to increase insulinotropic response which produces insulin, with the produced insulin being neuroprotective by direct neurotropic effects and by controlling stroke-related hyperglycemia  treat reperfusion injury. 
     
     
       2. The method of  claim 1  wherein the pharmaceutical carrier is selected from the group consisting of saline, buffered saline, dextrose, water, glycerol, ethanol, lactose, phosphate, mannitol, arginine, treholose, and combinations  mixtures thereof. 
     
     
       3. The method of  claim 1  wherein the administration commences within 4 hours of an ischemic event. 
     
     
       4. The method of  claim 1  wherein the administration of the composition is continuous and intravenously at 0.1 pmol/kg/min to 10 pmol/kg/min. 
     
     
       5. The method of  claim 1  wherein the administration of the composition is a bolus subcutaneous injection at 0.1 nmol/kg to 75 nmol/kg. 
     
     
       6. The method of  claim 1  wherein the administration is by a method selected from the group consisting of intravenous, intramuscular, intraperitoneal, subcutaneous or micropressure injection, deep lung insufflation, external or implant pump, depot injection, and other sustained release mechanisms,  buccal, and other cross skin and membrane mechanisms  and patch sustained release delivery mechanisms. 
     
     
       7. The method of  claim 1  wherein the composition is administered intravenously at a dose of 0.1 pmol/kg/min up to 10 pmol/kg/min. 
     
     
       8. The method of claim  7    1  further comprising concurrent administration of glucose. 
     
     
       9. The method of claim  7    1  further comprising concurrent administration of an oxygen scavenger. 
     
     
       10. A method of increasing insulinotropic response in ischemia injured brain cells comprising administering to an individual in need of such treatment a dose of 0.1 pmol/kg/min to 10 pmol/kg/min of a composition containing glucagon-like peptide-1 (GLP-1) and a pharmaceutical carrier for a time sufficient and under conditions effective to increase insulinotropic response which produces insulin, with the produced insulin being neuroprotective by direct neurotropic effects and by controlling stroke-related hyperglycemia. 
     
     
       11. The method of  claim 1  further comprising administering a thrombolytic agent. 
     
     
       12. A method of treating or ameliorating injury to brain cells in a subject following reperfusion after a period of ischemia comprising administering a composition comprising a glucagon-like peptide- 1  (GLP- 1 ) mimetic and a pharmaceutical carrier for a time sufficient and under conditions effective to treat or ameliorate said injury. 
     
     
       13. The method of  claim 12  wherein said GLP- 1  mimetic is GLP- 1  ( 1 - 37 ), GLP- 1 ( 1 - 36 ) amide, GLP- 1 ( 7 - 37 ), GLP- 1 ( 7 - 36 ) amide or mixtures thereof. 
     
     
       14. The method of  claim 12  wherein said GLP- 1  mimetic is an exendin. 
     
     
       15. The method of  claim 14  wherein said exendin is exendin- 3 . 
     
     
       16. The method of  claim 14  wherein said exendin is exendin- 4 . 
     
     
       17. The method of  claim 12  wherein said subject is not hyperglycemic. 
     
     
       18. A method of treating or ameliorating reperfusion injury to brain cells following stroke in a subject in need thereof, comprising administering a composition comprising an exendin to said subject for a time sufficient and under conditions effective to treat or ameliorate the reperfusion injury. 
     
     
       19. The method of  claim 18  wherein said exendin is exendin- 3 . 
     
     
       20. The method of  claim 18  wherein said exendin is exendin- 4 . 
     
     
       21. The method of  claim 18  wherein said subject is not hyperglycemic. 
     
     
       22. The method of  claim 18  wherein said stroke is ischemic. 
     
     
       23. The method of  claim 18  wherein said stroke is hemorrhagic. 
     
     
       24. The method of  claim 18  further comprising administering a thrombolytic agent. 
     
     
       25. The method of  claim 18  wherein the administration is by a method selected from the group consisting of intravenous, intramuscular, interperitoneal, subcutaneous or micropressure injection, deep lung insufflation, depot injection, buccal, patch, and sustained release delivery methods. 
     
     
       26. A method of treating or ameliorating injury to brain cells in a subject following a period of ischemia comprising administering a composition comprising an exendin and a pharmaceutical carrier. 
     
     
       27. The method of  claim 27  wherein said exendin is exendin- 4 . 
     
     
       28. The method of  claim 27  further comprising administering a thrombolytic agent. 
     
     
       29. The method of  claim 27  wherein the injury is caused by reperfusion.