Novel role for GLP-1 to mediate responses to disparate stressors

• US 20040116331A1
• Filed: 08/06/2003
• Published: 06/17/2004
• Est. Priority Date: 08/08/2002
• Status: Active Grant

• Current Assignee: Dʼalessio, David A., Kimberley P. Kinzig, Randy John Seeley
• Original Assignee: Dʼalessio, David A., Kimberley P. Kinzig, Randy John Seeley
• Inventors: DʼAlessio, David A., Seeley, Randy John, Kinzig, Kimberley P.
• Granted Patent: US 7,378,385 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons

Abstract

GLP-1 and GLP-1 receptor antagonists have been found to have a sedative or anxiolytic effect on the mammalian central nervous system. Conversely, GLP-1 and GLP-1 receptor agonists increase nervous system activity and the stress response. The invention relates, in one aspect, to the use of GLP-1 agonists and antagonists to modulate the stress response in a mammal. In an aspect GLP-1 and GLP-1 receptor antagonists are used to treat stress-related disorders.

Claims

1. A method of sedating a mammalian subject, the method comprising the step of administering an antagonist of GLP-1 or an antagonist of the GLP-1 receptor to the mammalian subject in an amount sufficient to produce a sedative or anxiolytic effect on the mammalian subject.

2. The method of claim 1, wherein the antagonist of GLP-1 or an antagonist of the GLP-1 receptor is administered to a human being.

3. The method of claim 1, wherein the antagonist of GLP-1 or an antagonist of the GLP-1 receptor is administered intracerebroventricularly.

4. The method of claim 3, wherein the mammalian subject is a human being.

5. The method of claim 1, wherein the antagonist of GLP-1 or an antagonist of the GLP-1 receptor is administered orally, subcutaneously, intramuscularly, or intravenously.

6. The method of claim 5, wherein the mammalian subject is a human being.

7. The method of claim 1, wherein the mammalian subject exhibits a stress-related disorder.

8. The method of claim 7, wherein said stress-related disorder is selected from the group consisting of:

anxiety, aggression, psychosis, seizures, panic attacks, hysteria, and sleep disorders.

9. The method of claim 7, wherein the mammalian subject is a human being.

10. A method of altering the circulating levels of adrenocorticotropin in a mammalian subject, the method comprising the step of administering a GLP-1 antagonist to the brain of the mammalian subject.

11. The method of claim 10, wherein the circulating levels of adrenocorticotropin increase.

12. A method of altering the circulating levels of a glucocorticoid in a mammalian subject, the method comprising the step of administering a GLP-1 antagonist to the brain of the mammalian subject.

13. The method of claim 12, wherein the circulating levels of a glucocorticoid increase.

14. The method of claim 12, wherein said glucocorticoid is corticosterone.

15. A method of altering the effect of a GLP-1 agonist in a mammalian subject, the method comprising the step of administering a CRH receptor antagonist to the mammalian subject.

16. The method of claim 15, wherein the effect of a GLP-1 agonist decreases.

17. A method to modulate the effects of an elevated level of a stress-activated hormone within a mammalian subject, the method comprising the step of administering a GLP-1R antagonist to the mammalian subject.

18. The method of claim 17, wherein said stress-activated hormone is adrenocorticotropin.

19. The method of claim 17, wherein said stress-activated hormone is a glucocorticoid.

20. The method of claim 17, wherein the effects of an elevated level of a stress-activated hormone decrease.

21. The method of claim 17, wherein said elevated stress-activated hormone results from internal stress.

22. The method of claim 17, wherein said elevated level of a stress-activated hormone results from external stress.

23. A method to decrease anxiety related behavior in a mammalian subject, the method comprising the step of administering GLP-1 antagonists to the mammalian subject.

24. A method to increase anxiety in a mammalian subject, the method comprising the step of administering GLP-1 agonists to the mammalian subject.

25. A method to modulate the stress response, said method comprising the step of administering a GLP-1 agonist to a mammalian subject.

26. The method of claim 25, wherein said GLP-1 agonist is administered to the brain.

27. The method of claim 25, wherein the stress response increases.

28. The method of claim 25, wherein said stress response comprises an endocrine response.

29. The method of claim 25, wherein said stress response comprises an anxiety response.

30. The method of claim 25, wherein said stress response comprises an endocrine response and an anxiety response.

31. A method to preferentially modulate the endocrine response said method comprising the step of administering a GLP-1 agonist to the paraventricular nucleus of the hypothalamus.

32. The method of claim 31, wherein the endocrine response increases.

33. A method to preferentially modulate the anxiety response said method comprising the step of administering a GLP-1 agonist to the central nucleus of the amygdala.

34. The method of claim 33, wherein said anxiety response increases.

35. A method to modulate the stress response said method comprising the step of administering a GLP-1 antagonist to a mammalian subject.

36. The method of claim 35, wherein the GLP-1 antagonist is administered to the brain.

37. The method of claim 35, wherein the stress response decreases.

38. The method of claim 35, wherein said stress response is an endocrine response.

39. The method of claim 35, wherein said stress response is an anxiety response.

40. The method of claim 35, wherein said stress response comprises an endocrine response and an anxiety response.

41. A method to treat a stress-related disorder, said method comprising the step of administering a GLP1 antagonist to a mammalian subject exhibiting a stress-related disorder.

42. The method of claim 41, wherein said GLP-1 antagonist is administered intracerebroventricularly, orally, subcutaneously, intramuscularly, or intravenously.

43. A method to treat a stress-related disorder, said method comprising the step of administering a therapeutically effective amount of a GLP-1 receptor antagonist to a mammalian subject exhibiting a stress-related disorder.

44. The method of claim 43, wherein said GLP-1 receptor antagonist is administered intracerebroventricularly, orally, subcutaneously, intramuscularly, or intravenously.

45. The method of claim 43, wherein said therapeutically effective amount of a GLP-1 receptor antagonist is in the range of 0.001 to 30 mg/kg body weight.

46. The method of claim 43, wherein said therapeutically effective amount of a GLP-1 receptor antagonist is in the range of 0.01 to 3 mg/kg body weight.

47. The method of claim 43, wherein said therapeutically effective amount of a GLP-1 receptor antagonist is in the range of 0.01 to 0.5 mg/kg body weight.

48. The method of claim 43, wherein said therapeutically effective amount of a GLP-1 receptor antagonist is in the range of 0.01 to 30 mg/kg body weight.

49. A method to preferentially modulate the endocrine response to stress said method comprising the step of administering a GLP-1 agonist to a mammalian subject.

50. The method of claim 49, wherein said endocrine response increases.