Methods of limiting apoptosis of cells

• US 20030044413A1
• Filed: 09/18/2002
• Published: 03/06/2003
• Est. Priority Date: 08/15/2000
• Status: Abandoned Application

• Current Assignee: Regents of The University of Minnesota (University of Minnesota)
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Fan, Guangsheng, Rodrigues, Cecilia M.P., Kren, Betsy T., Steer, Clifford J.
• Application Number:
  US10/246,025
• Publication Number:
  US 20030044413A1
• Time in Patent Office: Days
• US Class Current: 424/145.1
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin

Abstract

Methods for limiting apoptosis in a cell population by contacting such cells with a hydrophilic bile acid, such as ursodeoxycholic acid (UDCA), salts thereof, and analogs thereof (e.g., glyco- and tauro-ursodeoxycholic acid).

Claims

1. A method for limiting apoptosis of a mammalian cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound selected from the group of ursodeoxycholic acid, a salt thereof, an analog thereof, and a combination thereof, wherein the apoptosis is induced by a nonmembrane damaging agent.

2. The method of claim 1 wherein the nonmembrane damaging agent is selected from the group of TGF-β

1, anti-Fas antibody, and okadaic acid.

3. The method of claim 1 wherein the cell population comprises hepatocytes.

4. The method of claim 1 wherein the cell population comprises astrocytes.

5. The method of claim 1 wherein the contacting step occurs in vitro.

6. The method of claim 1 wherein the contacting step occurs in vivo.

7. The method of claim 1 wherein the cell population is a human cell population.

8. The method of claim 1 wherein the step of contacting comprises administering to a patient an effective amount of an apoptotic limiting compound selected from the group of ursodeoxycholic acid, a salt thereof, an analog thereof, and a combination thereof.

9. The method of claim 8 wherein the apoptotic limiting compound is administered in combination with a pharmaceutically acceptable carrier.

10. The method of claim 9 wherein the step of administering comprises administering parenterally.

11. The method of claim 9 wherein the step of administering comprises administering orally.

12. A method for limiting apoptosis of a mammalian cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound selected from the group of ursodeoxycholic acid, a salt thereof, an analog thereof, and a combination thereof, wherein the apoptosis is induced by ethanol.

13. A method for limiting apoptosis of a human cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound selected from the group of hydrophilic bile acid, a salt thereof, an analog thereof, and a combination thereof, wherein the apoptosis is induced by a hydrophobic bile acid.

14. A method for limiting apoptosis of a mammalian cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound selected from the group of hydrophilic bile acid, a salt thereof, an analog thereof, and a combination thereof, wherein the apoptosis is induced by TGF-β

1, anti-Fas antibody, okadaic acid, or unconjugated bilirubin.

15. A method for inhibiting apoptosis associated with a nonliver disease in vivo, the method comprising administering ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

16. The method of claim 15 wherein the nonliver disease is an autoimmune disease, a cardiovascular disease, or a neurodegenerative disease.

17. A method of reducing expression of c-myc in a cell, the method comprising contacting the cell with an effective amount of ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

18. A method of increasing levels of Bcl-X_L in a cell, the method comprising contacting the cell with an effective amount of ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

19. A method of inhibiting Bax translocation from the cytoplasm of a cell to a mitochondrial membrane, the method comprising contacting the cell with an effective amount of ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

20. A method for limiting apoptosis of a mammalian cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound selected from the group of ursodeoxycholic acid, a salt thereof, an analog thereof, and a combination thereof, wherein the apoptosis is induced by a membrane damaging agent selected from the group consisting of unconjugated bilirubin, conjugated bilirubin, and a combination thereof.

21. The method of claim 20 wherein the cell population comprises hepatocytes.

22. The method of claim 20 wherein the cell population comprises astrocytes.

23. The method of claim 20 wherein the contacting step occurs in vitro.

24. The method of claim 20 wherein the contacting step occurs in vivo.

25. The method of claim 20 wherein the cell population is a human cell population.

26. The method of claim 20 wherein the step of contacting comprises administering to a patient an effective amount of an apoptotic limiting compound selected from the group of ursodeoxycholic acid, a salt thereof, an analog thereof, and a combination thereof.

27. The method of claim 26 wherein the apoptotic limiting compound is administered in combination with a pharmaceutically acceptable carrier.

28. The method of claim 27 wherein the step of administering comprises administering parenterally.

29. The method of claim 27 wherein the step of administering comprises administering orally.

30. A method of treating a patient with a neurodegenerative disease, the method comprising administering to a patient ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

31. The method of claim 30 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in combination with a pharmaceutically acceptable carrier.

32. The method of claim 30 wherein the step of administering comprises administering parenterally.

33. The method of claim 30 wherein the step of administering comprises administering orally.

34. The method of claim 30 wherein the analog of ursodeoxycholic acid is glyco-ursodeoxycholic acid.

35. The method of claim 30 wherein the analog of ursodeoxycholic acid is tauro-ursodeoxycholic acid.

36. The method of claim 30 wherein the patient is a human patient.

37. The method of claim 30 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in a nasal spray formulation.

38. The method of claim 30 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in an ophthalmic formulation.

39. The method of claim 30 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in a topical formulation.

40. A method of treating a patient with a stroke injury, the method comprising administering to the patient ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

41. The method of claim 40 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in combination with a pharmaceutically acceptable carrier.

42. The method of claim 40 wherein the step of administering comprises administering parenterally.

43. The method of claim 40 wherein the step of administering comprises administering orally.

44. The method of claim 40 wherein the analog of ursodeoxycholic acid is glyco-ursodeoxycholic acid.

45. The method of claim 40 wherein the analog of ursodeoxycholic acid is tauro-ursodeoxycholic acid.

46. The method of claim 40 wherein the patient is a human patient.

47. A method of treating a patient with an autoimmune disease, the method comprising administering to the patient ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

48. The method of claim 47 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in combination with a pharmaceutically acceptable carrier.

49. The method of claim 47 wherein the step of administering comprises administering parenterally.

50. The method of claim 47 wherein the step of administering comprises administering orally.

51. The method of claim 47 wherein the analog of ursodeoxycholic acid is glyco-ursodeoxycholic acid.

52. The method of claim 47 wherein the analog of ursodeoxycholic acid is tauro-ursodeoxycholic acid.

53. The method of claim 47 wherein the patient is a human patient.

54. The method of claim 47 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in a nasal spray formulation.

55. The method of claim 47 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in an ophthalmic formulation.

56. The method of claim 47 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in a topical formulation.

57. A method of treating a patient with a cardiovascular disease or a cerebrovascular disease, the method comprising administering to the patient ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

58. The method of claim 57 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in combination with a pharmaceutically acceptable carrier.

59. The method of claim 57 wherein the step of administering comprises administering parenterally.

60. The method of claim 57 wherein the step of administering comprises administering orally.

61. The method of claim 57 wherein the analog of ursodeoxycholic acid is glyco-ursodeoxycholic acid.

62. The method of claim 57 wherein the analog of ursodeoxycholic acid is tauro-ursodeoxycholic acid.

63. The method of claim 57 wherein the patient is a human patient.

64. The method of claim 57 wherein the ursodeoxycholic acid, a salt thereof an analog thereof, or a combination thereof is administered in a nasal spray formulation.

65. A method of treating a patient prophylactically for an autoimmune disease, a neurodegenerative disease, a cardiovascular disease, or a cerebrovascular disease, the method comprising administering to the patient ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof.

66. The method of claim 65 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in combination with a pharmaceutically acceptable carrier.

67. The method of claim 65 wherein the step of administering comprises administering parenterally.

68. The method of claim 65 wherein the step of administering comprises administering orally.

69. The method of claim 65 wherein the analog of ursodeoxycholic acid is glyco-ursodeoxycholic acid.

70. The method of claim 65 wherein the analog of ursodeoxycholic acid is tauro-ursodeoxycholic acid.

71. The method of claim 65 wherein the patient is a human patient.

72. The method of claim 65 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in a nasal spray formulation.

73. The method of claim 65 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in an ophthalmic formulation.

74. The method of claim 65 wherein the ursodeoxycholic acid, a salt thereof, an analog thereof, or a combination thereof is administered in a topical formulation.

75. A method of limiting apoptosis of a mammalian cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound that modulates mitochondrial membrane perturbation.

76. The method of claim 75 wherein the contacting step occurs in vitro.

77. The method of claim 75 wherein the contacting step occurs in vivo.

78. The method of claim 75 wherein the cell population is a human cell population.

79. A method of limiting apoptosis of a mammalian cell population, the method comprising contacting the cell population with an effective amount of an apoptotic limiting compound that modulates mitochondrial transmembrane potential and reactive oxygen species production.

80. The method of claim 79 wherein the contacting step occurs in vitro.

81. The method of claim 79 wherein the contacting step occurs in vivo.

82. The method of claim 79 wherein the cell population is a human cell population.

83. A method of inhibiting Bax translocation from the cytoplasm of a cell to a mitochondrial membrane;

the method comprising contacting the cell with an effective amount of a compound that limits apoptosis through a mitochondrial membrane.