Use of ghrelin or functional ghrelin receptor agonists to prevent and treat stress-sensitive psychiatric illness
The invention relates to methods of treating stress-sensitive psychiatric diseases arising from trauma in a subject by enhancing ghrelin signaling in the BLA of the subject. The invention also relates to methods of reversing ghrelin resistance.
1. A method of treating a stress-sensitive psychiatric disease in a subject comprising administering to the subject a therapeutically effective amount of ghrelin or a functional ghrelin receptor (GHSR) agonist, within a memory consolidation period following a trauma exposure, wherein the stress-sensitive psychiatric disease is selected from the group consisting of: Post-traumatic Stress Disorder (PTSD), Depressive Disorder, Major Depressive Disorders, Bipolar Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorders, and Trichotillomania, wherein the functional GHSR agonist is not adenosine.
2. The method of claim 1 , wherein the ghrelin or the functional GHSR agonist is administered within 24 hours following the trauma exposure.
3. The method of claim 1 , wherein the ghrelin or the functional GHSR agonist is administered within 48 hours following the trauma exposure.
4. The method of claim 1 , wherein the ghrelin or the functional GHSR agonist is administered within 1 week following the trauma exposure.
5. The method of claim 1 , wherein ghrelin is administered to the subject.
6. The method of claim 5 , wherein the ghrelin is in the form of acyl-ghrelin.
7. The method of claim 1 , wherein a functional GHSR agonist is administered to the subject.
8. The method of claim 7 , wherein the functional GHSR agonist is selected from the group consisting of: alexamorelin, Anamorelin, Capromorelin, CP-464709, Cortistatin-14, Examorelin (hexarelin), Growth Hormone Releasing Peptide-1 (GHRP-1), Growth Hormone Releasing Peptide-3 (GHRP-3), Growth Hormone Releasing Peptide-4 (GHRP-4), Growth Hormone Releasing Peptide 5 (GHRP-5), Growth Hormone Releasing Peptide-6 (GHRP-6), Ibutamoren (MK-677), Ibutamoren mesylate (IBU), Ipamorelin, L-692585, LY-426410, LY-444711, Macimorelin, Pralmorelin, Relamorelin, SM-130,686, Tabimorelin, Ulimorelin, and combination thereof.
9. The method of claim 8 , wherein the functional GHSR agonist is ibutamoren mesylate (IBU).
10. The method of claim 1 , wherein the administering is via systemic administration, injection, or infusion directly into the BLA of the subject.
11. The method of claim 1 , wherein the subject is unstressed.
12. The method of claim 1 , wherein the subject is a human.
13. A method of treating a stress-sensitive psychiatric disease in a subject comprising administering to the subject a therapeutically effective amount of ghrelin or a functional ghrelin receptor (GHSR) agonist, within a memory re-consolidation period following re-activation of a memory of a previous trauma exposure,
wherein the stress-sensitive psychiatric disease is selected from the group consisting of: Post-traumatic Stress Disorder (PTSD), Depressive Disorder, Major Depressive Disorders, Bipolar Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorders, and Trichotillomania, wherein the ghrelin agonist is not adenosine.
14. The method of claim 13 , wherein the ghrelin or the functional GHSR agonist is administered within 24 hours following the re-activation of a memory of a previous trauma exposure.
15. The method of claim 13 , wherein the ghrelin or the functional GHSR agonist is administered within 48 hours following the re-activation of a memory of a previous trauma exposure.
16. The method of claim 13 , wherein the ghrelin or the functional GHSR agonist is administered within 1 week following the re-activation of a memory of a previous trauma exposure.
17. The method of claim 13 , wherein ghrelin is administered to the subject.
18. The method of claim 17 , wherein the ghrelin is in the form of acyl-ghrelin.
19. The method of claim 13 , wherein a functional GHSR agonist is administered to the subject.
20. The method of claim 19 , wherein the functional GHSR agonist is selected from the group consisting of: alexamorelin, Anamorelin, Capromorelin, CP-464709, Cortistatin-14, Examorelin (hexarelin), Growth Hormone Releasing Peptide-1 (GHRP-1), Growth Hormone Releasing Peptide-3 (GHRP-3), Growth Hormone Releasing Peptide-4 (GHRP-4), Growth Hormone Releasing Peptide 5 (GHRP-5), Growth Hormone Releasing Peptide-6 (GHRP-6), Ibutamoren (MK-677), Ibutamoren mesylate (IBU), Ipamorelin, L-692585, LY-426410, LY-444711, Macimorelin, Pralmorelin, Relamorelin, SM-130,686, Tabimorelin, Ulimorelin, and combination thereof.
21. The method of claim 20 , wherein the functional GHSR agonist is ibutamoren mesylate (IBU).
22. The method of claim 13 , comprising administering to the subject a therapeutically effective amount of ghrelin and a functional ghrelin receptor (GHSR) agonist.
23. The method of claim 13 , wherein the administering is via systemic administration, injection, or infusion directly into the basolateral complex of the amygdala (BLA) of the subject.
24. The method of claim 13 , wherein the subject is unstressed.
25. The method of claim 13 , wherein the subject is a human.
26. The method of claim 13 , wherein the memory of the previous trauma exposure is a long-term memory.
27. A method of treating a stress-sensitive psychiatric disease in a subject who has been exposed to chronic stress, comprising:
(a) upregulating the endogenous level of ghrelin receptors (GHSRs) in the subject, the upregulating comprising administering to the subject a therapeutically effective amount of a ghrelin antagonist or a GHSR antagonist; and
(b) administering to the subject a therapeutically effective amount of ghrelin or a functional GHSR agonist, within a memory consolidation period following a trauma exposure, wherein the stress-sensitive psychiatric disease is selected from the group consisting of: Post-traumatic Stress Disorder (PTSD), Depressive Disorder, Major Depressive Disorders, Bipolar Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorders, and Trichotillomania.
28. The method of claim 27 , wherein the ghrelin antagonist is an anti-ghrelin vaccine.
29. The method of claim 27 , wherein the ghrelin antagonist inhibits ghrelin acylation.
30. The method of claim 27 , wherein the ghrelin or the functional GHSR agonist is administered within 24 hours following the trauma exposure.
31. The method of claim 27 , wherein the ghrelin or the functional GHSR agonist is administered within 48 hours following the trauma exposure.
32. The method of claim 27 , wherein the ghrelin or the functional GHSR agonist is administered within 1 week following the trauma exposure.
33. The method of claim 27 , wherein the functional GHSR agonist is selected from the group consisting of: Adenosine, alexamorelin, Anamorelin, Capromorelin, CP-464709, Cortistatin-14, Examorelin (hexarelin), Growth Hormone Releasing Peptide-1 (GHRP-1), Growth Hormone Releasing Peptide-3 (GHRP-3), Growth Hormone Releasing Peptide-4 (GHRP-4), Growth Hormone Releasing Peptide-5 (GHRP-5), Growth Hormone Releasing Peptide-6 (GHRP-6), Ibutamoren (MK-677), Ibutamoren mesylate (IBU), Ipamorelin, L-692585, LY-426410, LY-444711, Macimorelin, Pralmorelin, Relamorelin, SM-130,686, Tabimorelin, Ulimorelin, and combination thereof.
34. The method of claim 27 , wherein the step of upregulating further comprises measuring the endogenous ghrelin levels in the subject.
35. The method of claim 27 , wherein the subject who have been exposed to chronic stress has elevated endogenous ghrelin levels compared to that of a control.
36. The method of claim 35 , wherein the control is a subject not exposed to chronic stress.
37. The method of claim 27 , wherein the subject is a human.
38. The method of claim 29 , wherein the ghrelin antagonist inhibits ghrelin O-acyltransferase (GOAT).
39. The method of claim 38 , wherein the ghrelin antagonist is an anti-GOAT vaccine.