Inhibition of inflammatory cytokine production by stimulation of brain muscarinic receptors

• US 20040048795A1
• Filed: 02/26/2003
• Published: 03/11/2004
• Est. Priority Date: 02/26/2002
• Status: Abandoned Application

• Current Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Original Assignee: North Shore-Long Island Jewish Research Institute
• Inventors: Tracey, Kevin J., Ivanova, Svetlana M.
• Application Number:
  US10/375,696
• Publication Number:
  US 20040048795A1
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 41/17 by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• CPC Class Codes: A61N 1/32 alternating or intermittent currents applying electric fields by inductive or capacitive coupling A61N1/40; microwave apparatus A61N5/02
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
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• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
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• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 33/04 : Amoebicides
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Methods for inhibiting pro-inflammatory cytokine release or inflammation in a vertebrate are provided. The methods comprise activating a brain muscarinic receptor of the vertebrate, or directly stimulating a vagus nerve pathway in the brain of the vertebrate. Also provided are methods for conditioning a vertebrate to inhibit the release of a pro-inflammatory cytokine or reduce inflammation in the vertebrate upon experiencing a sensory stimulus. The methods comprise (a) activating a muscarinic brain receptor or directly stimulating the vagus nerve pathway in the brain of the vertebrate and providing the sensory stimulus to the vertebrate within a time period sufficient to create an association between the stimulus and the activation of the brain muscarinic receptor; and (b) repeating step (a) at sufficient time intervals and duration to reinforce the association sufficiently for the inflammation to be reduced by the sensory stimulus alone.

Claims

1. A method of inhibiting release of a pro-inflammatory cytokine in a vertebrate, at risk for or having a condition mediated by an inflammatory cytokine cascade, the method comprising activating a brain muscarinic receptor in the vertebrate.

2. The method of claim 1, wherein the pro-inflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-1α

, IL-1β

, IL-6, IL-18, HMG-B1, MIP-1α

, MIP-1β

, MIF, interferon-γ

, and PAF.

3. The method of claim 1, wherein the pro-inflammatory cytokine is TNF.

4. The method of claim 1, wherein the vertebrate is a human.

5. The method of claim 1, wherein the condition is selected from the group consisting of appendicitis, peptic ulcers, gastric ulcers, duodenal ulcers, peritonitis, pancreatitis, inflammatory bowel disease, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, enteritis, Whipple'"'"'s disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopic silicovolcanoconiosis, alveolitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasculitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritis, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosus, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger'"'"'s disease, Retier'"'"'s syndrome, and Hodgkins disease.

6. The method of claim 5, wherein the inflammatory bowel disease is selected from the group consisting of ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, and Crohn'"'"'s disease.

7. The method of claim 5, wherein the arthritis is rheumatoid arthritis.

8. The method of claim 1, wherein the condition is selected from the group consisting of allograft rejection, arthritis, asthma, lupus, adult respiratory distress syndrome, pancreatitis, peritonitis, burns, Behcet'"'"'s disease, graft versus host disease, inflammatory bowel disease, multiple sclerosis, organ ischemia, reperfusion injury, myocardial ischemia, and cachexia.

9. The method of claim 1, wherein the condition is shock, chronic obstructive pulmonary disease, or psoriasis.

10. The method of claim 1, wherein the condition is sepsis.

11. The method of claim 1, wherein the brain muscarinic receptor is selected from the group consisting of an M1, an M2, and an M4 receptor.

12. The method of claim 1, wherein the brain muscarinic receptor is activated by administering a muscarinic agonist to the vertebrate.

13. The method of claim 12, wherein the muscarinic agonist is administered directly to the brain of the vertebrate.

14. The method of claim 12, wherein the muscarinic agonist can cross the blood-brain barrier of the vertebrate, and wherein the agonist is administered enterically or parentally, or is injected into the bloodstream of the vertebrate.

15. The method of claim 12, wherein the muscarinic agonist is selected from the group consisting of muscarine, McN-A-343, and MT-3.

16. A method of inhibiting release of a pro-inflammatory cytokine in a vertebrate at risk for or having a condition mediated by an inflammatory cytokine cascade, the method comprising directly stimulating a vagus nerve pathway in the brain of the vertebrate.

17. The method of claim 16, wherein the vagus nerve pathway is stimulated electrically.

18. A method of treating an inflammatory disease in a vertebrate, the method comprising activating a brain muscarinic receptor in the vertebrate at a level sufficient to inhibit release of a pro-inflammatory cytokine.

19. The method of claim 18, wherein the vertebrate is a human.

20. The method of claim 18, wherein the inflammatory disease is mediated by an inflammatory cytokine cascade.

21. The method of claim 18, wherein the inflammatory disease is selected from the group consisting of appendicitis, peptic ulcers, gastric ulcers, duodenal ulcers, peritonitis, pancreatitis, inflammatory bowel disease, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, enteritis, Whipple'"'"'s disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopic silicovolcanoconiosis, alveolitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasculitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritis, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, synovitis, myasthenia gravis, thyroiditis, systemic lupus erythematosus, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger'"'"'s disease, Retier'"'"'s syndrome, and Hodgkins disease.

22. The method of claim 21, wherein the inflammatory bowel disease is selected from the group consisting of ulcerative colitis, pseudomembranous colitis, acute colitis, ischemic colitis, and Crohn'"'"'s disease.

23. The method of claim 21, wherein the arthritis is rheumatoid arthritis.

24. The method of claim 18, wherein the inflammatory disease is selected from the group consisting of allograft rejection, arthritis, asthma, lupus, adult respiratory distress syndrome, pancreatitis, peritonitis, burns, Behcet'"'"'s disease, graft versus host disease, inflammatory bowel disease, multiple sclerosis, organ ischemia, reperfusion injury, myocardial ischemia, and cachexia.

25. The method of claim 18, wherein the inflammatory disease is shock, chronic obstructive pulmonary disease, or psoriasis.

26. The method of claim 18, wherein the condition is sepsis.

27. The method of claim 18, wherein the brain muscarinic receptor is selected from the group consisting of an M1, an M2, and an M4 receptor.

28. The method of claim 18, wherein the brain muscarinic receptor is activated by administering a muscarinic agonist to the vertebrate.

29. The method of claim 28, wherein the muscarinic agonist is administered directly to the brain of the vertebrate.

30. The method of claim 28, wherein the muscarinic agonist can cross the blood-brain barrier of the vertebrate, and wherein the agonist is administered enterically, parentally, or is injected into the bloodstream of the vertebrate.

31. The method of claim 28, wherein the muscarinic agonist is selected from the group consisting of muscarine, McN-A-343, and MT-3.

32. A method of treating an inflammatory disease in a vertebrate, the method comprising directly stimulating a vagus nerve pathway in the brain of the vertebrate in an amount sufficient to inhibit release of a pro-inflammatory cytokine in the vertebrate.

33. The method of claim 32, wherein the vagus nerve pathway is stimulated electrically.

34. A method of inhibiting apoptosis of a cardiac myocyte in a vertebrate at risk for cardiac myocyte apoptosis, the method comprising activating a brain muscarinic receptor in the vertebrate.

35. A method of inhibiting apoptosis of a cardiac myocyte in a vertebrate at risk for cardiac myocyte apoptosis, the method comprising directly stimulating a vagus nerve pathway in the brain of the vertebrate.

36. A method of conditioning a vertebrate to inhibit the release of a pro-inflammatory cytokine upon experiencing a sensory stimulus, the method comprising

(a) activating a brain muscarinic receptor in the vertebrate and providing the sensory stimulus to the vertebrate within a time period sufficient to create an association between the stimulus and the activation of the brain muscarinic receptor;

and

(b) repeating step (a) at sufficient time intervals and duration to reinforce the association sufficiently for the pro-inflammatory cytokine release to be inhibited by the sensory stimulus alone.

37. A method of conditioning a vertebrate to inhibit the release of a pro-inflammatory cytokine upon experiencing a sensory stimulus, the method comprising

(a) directly stimulating a vagus nerve pathway in the brain of the vertebrate and providing the sensory stimulus to the vertebrate within a time period sufficient to create an association between the stimulus and the stimulation of a vagus nerve pathway;

and

(b) repeating step (a) at sufficient time intervals and duration to reinforce the association sufficiently for the pro-inflammatory cytokine release to be inhibited by the sensory stimulus alone.

38. A method of conditioning a vertebrate to reduce inflammation in the vertebrate upon experiencing a sensory stimulus, the method comprising

(a) activating a brain muscarinic receptor in the vertebrate and providing the sensory stimulus to the vertebrate within a time period sufficient to create an association between the stimulus and the activation of the brain muscarinic receptor;

and

(b) repeating step (a) at sufficient time intervals and duration to reinforce the association sufficiently for the inflammation to be reduced by the sensory stimulus alone.

39. A method of conditioning a vertebrate to reduce inflammation in the vertebrate upon experiencing a sensory stimulus, the method comprising

(a) directly stimulating a vagus nerve pathway in the brain of the vertebrate and providing the sensory stimulus to the vertebrate within a time period sufficient to create an association between the stimulus and the activation of the brain muscarinic receptor;

and

(b) repeating step (a) at sufficient time intervals and duration to reinforce the association sufficiently for the inflammation to be reduced by the sensory stimulus alone.