Methods of using small molecule compounds for neuroprotection

• US 20070203079A1
• Filed: 11/21/2006
• Published: 08/30/2007
• Est. Priority Date: 11/21/2005
• Status: Abandoned Application

• Current Assignee: University of Alabama (University of Alabama System)
• Original Assignee: University of Alabama (University of Alabama System)
• Inventors: Caldwell, Guy, Caldwell, Kim, Cao, Songsong
• Application Number:
  US11/603,924
• Publication Number:
  US 20070203079A1
• Time in Patent Office: Days
• US Class Current: 514/27
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4741 condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Methods are provided for preventing neurodegeneration and neuronal loss by administering compositions comprising small molecule compounds with the effect of preventing neurodegeneration and neuronal loss. In one aspect of the invention, the methods and compositions are also useful for treating neurodegenerative diseases. Small molecule compounds provide an important treatment option because of their stability, ease of use in both manufacture and formulation, ease of administration, and patient compliance. The small molecule compound compositions of the present invention may include topoisomerase II inhibitors, bacterial transpeptidase inhibitors, calcium channel antagonists, cyclooxygenase inhibitors, folic acid synthesis inhibitors, or sodium channel blockers and functional analogues thereof that have an effect on neurodegeneration. The compositions of the present invention may be administered prophylactically before the onset of clinical symptoms or after clinical symptoms of a neurodegenerative disease have manifested.

Claims

1. A method for preventing neurodegeneration and neuronal loss associated with protein misfolding or aggregation by administering a composition comprising an effective amount of a small molecule compound to a mammal in need of treatment for preventing neurodegeneration and neuronal loss associated with protein misfolding or aggregation, wherein the small molecule compound has the effect of preventing neurodegeneration and neuronal loss associated with protein misfolding or aggregation, and

wherein the small molecule compound comprises a topoisomerase II inhibitor, bacterial transpeptidase inhibitor, calcium channel antagonist, cyclooxygenase inhibitor, folic acid synthesis inhibitor, or sodium channel blocker and functional analogues thereof.

2. The method of claim 1 wherein the topoisomerase II inhibitor comprises lomefloxacin, cinoxacin, amsacrine, etoposide, teniposide, oxolinic acid, nalidixic acid, suramin, merbarone, genistein, epirubicin HCl, ellipticine, doxorubicin, aurintricarboxylic acid or pharmaceutically acceptable salts thereof.

3. The method of claim 2 wherein the topoisomerase II inhibitor comprises oxolinic acid or nalidixic acid.

4. The method of claim 3 wherein the oxolinic acid is administered at a dosage between about 10 mg/kg and about 40 mg/kg.

5. The method of claim 3 wherein the nalidixic acid is administered at a dosage between about 1 gram/day and about 5 grams/day.

6. The method of claim 1 wherein the bacterial transpeptidase inhibitor comprises ampicillin, cloxacillin, piperacillin, amoxicillin, cefadroxil, dicloxyacillin, carbenicillin, penicillin, metampicillin, amoxicillin, cefoxatin or pharmaceutically acceptable salts thereof.

7. The method of claim 6 wherein the bacterial transpeptidase inhibitor comprises metampicillin.

8. The method of claim 7 wherein the metampicillin is administered at a dosage between about 250 mg/kg and about 500 mg/kg every 8 hours.

9. The method of claim 1 wherein the calcium channel blocker comprises nimodipine, diproteverine, verapamil, nitrendipine, diltiazem, mioflazine, loperamide, flunarizine, bepridil, lidoflazine, CERM-196, R-58735, R-56865, ranolazine, nisoldipine, nicardipine, PN200-110, felodipine, amlodipine, R-(−

)-202-791, or R-(+) Bay K-8644 or pharmaceutically acceptable salts thereof.

10. The method of claim 9 wherein the calcium channel blocker comprises loperamide.

11. The method of claim 10 wherein the loperamide is administered at a dosage between about 1 mg/kg and about 5 mg/kg.

12. The method of claim 1 wherein the cyclooxygenase inhibitor comprises naproxen, flufenamic acid, tolfenamic acid, fenbufen, ketoprofen, phenacetin, dipyrone, flurbiprofen, meclofenamide, piroxicam, indomethacine or pharmaceutically acceptable salts thereof.

13. The method of claim 12 wherein the cyclooxygenase inhibitor comprises meclofenamide.

14. The method of claim 13 wherein the meclofenamide is administered at a dosage between about 25 mg/kg and about 75 mg/kg.

15. The method of claim 1 wherein the folic acid synthesis inhibitor comprises sulfonamides, dapsone, trimethoprim, diaveridine, pyrimethamine, methotrexate, or pharmaceutically acceptable salts thereof.

16. The method of claim 15 wherein the folic acid synthesis inhibitor comprises mafenide.

17. The method of claim 16 wherein the mafenide is administered at a dosage between about 250 mg/kg and about 750 mg/kg every 6 hours.

18. The method of claim 1 wherein the sodium channel blocker comprises lidocaine, dyclonine HCl, mexilitine, phenyloin, ketamine, flecainide, amantadine or pharmaceutically acceptable salts thereof.

19. The method of claim 18 wherein the sodium channel blocker comprises dyclonine HCl.

20. The method of claim 19 wherein the dyclonine HCl is administered at a dosage between about 2 mg/kg and about 3 mg/kg every 2 hours.

21. The method of claim 1 wherein the small molecule compound is administered by inhalation, transdermal, oral, rectal, transmucosal, intestinal, or parenteral routes.

22. The method of claim 1, wherein the small molecule compound is administered to the mammal after the onset of neurodegeneration and neuronal loss associated with protein misfolding or aggregation.

23. The method of claim 1 wherein the small molecule compound modulates the activity of a torsin protein.

24. The method of claim 23 wherein the small molecule compound modulates the activity of a wild-type torsinA protein.

25. The method of claim 23 wherein the small molecule compound modulates the activity of a mutant torsinA protein.

26. The method of claim 1 wherein the protein misfolding or aggregation is associated with a neurodegenerative disease comprising amyotrophic lateral sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, prion disease, polyglutamine expansion diseases, spinocerebellar ataxia, spinal and bulbar muscular atrophy, spongiform encephalopathy, tauopathy, Huntington'"'"'s disease, or dystonia.

27. A method for preventing neurodegeneration and neuronal loss associated with reactive oxygen species by administering a composition comprising an effective amount of a small molecule compound to a mammal in need of treatment for preventing neurodegeneration and neuronal loss associated with reactive oxygen species, wherein the small molecule compound has the effect of preventing neurodegeneration and neuronal loss associated with reactive oxygen species, and

wherein the small molecule compound comprises topoisomerase II inhibitors, bacterial transpeptidase inhibitors, calcium channel antagonists, cyclooxygenase inhibitors, folic acid synthesis inhibitors, or sodium channel blockers and functional analogues thereof.

28. The method of claim 27 wherein the folic acid synthesis inhibitor comprises mafenide HCl, sulfacetamide sodic hydrate, sulfadiazine, sulfaguanidine, sulfathiazole, sulfamethoxazole, sulfabenzamide or functional analogues thereof.

29. The method of claim 28 wherein the folic acid synthesis inhibitor comprises mafenide.

30. The method of claim 29 wherein the mafenide is administered at a dosage between about 250 mg/kg and about 500 mg/kg.

31. The method of claim 27 wherein the sodium channel blocker comprises lidocaine, dyclonine HCl, mexilitine, phenyloin, ketamine, flecainide, amantadine or pharmaceutically acceptable salts thereof.

32. The method of claim 31 wherein the sodium channel blocker comprises lidocaine.

33. The method of claim 32 wherein the lidocaine is administered at a dosage between about 1 mg/kg and about 50 mg/kg.

34. The method of claim 27 wherein the cyclooxygenase inhibitor comprises flurbiprofen, meclofenamide, piroxicam, indomethacine or pharmaceutically acceptable salts thereof.

35. The method of claim 34 wherein the cyclooxygenase inhibitor comprises meclofenamide.

36. The method of claim 35 wherein the meclofenamide is administered at a dosage between about 25 mg/kg and about 75 mg/kg.

37. The method of claim 27 wherein the bacterial transpeptidase inhibitor comprises ampicillin, penicillin, cefadroxil, amoxicillin, piperacillin, cloxacillin carbenicillin, metampicillin, dicloxyacillin, amoxicillin, cefoxatin or pharmaceutically acceptable salts thereof.

38. The method of claim 37 wherein the bacterial transpeptidase inhibitor comprises metampicillin.

39. The method of claim 38 wherein the metampicillin is administered at a dosage between about 250 mg/kg and about 500 mg/kg every 8 hours.

40. The method of claim 27 wherein the small molecule compound is administered by inhalation, transdermal, oral, rectal, transmucosal, intestinal, or parenteral routes.

41. The method of claim 27 wherein the reactive oxygen species is associated with a neurodegenerative disease comprising amyotrophic lateral sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, prion diseases, polyglutamine expansion diseases, spinocerebellar ataxia, spinal and bulbar muscular atrophy, spongiform encephalopathy, tauopathy, Huntington'"'"'s disease, or dystonia.

42. The method of claim 27 wherein the small molecule compound further comprises a reactive oxygen species scavenger or at least one neurotrophic factor.

43. The method of claim 42, wherein the reactive oxygen species scavenger comprises coenzyme Q, vitamin E, vitamin C, pyruvate, melatonin, niacinamide, N-acetylcysteine, glutathione, or a nitrone.

44. The method of claim 27, wherein the small molecule compound is administered to the mammal after the onset of neurodegeneration and neuronal loss associated with reactive oxygen species.

45. The method of claim 27, wherein the small molecule compound modulates the neuroprotective activity of a torsin protein.

46. The method of claim 45, wherein the small molecule compound indirectly modulates the neuroprotective activity of the torsin protein.

47. The method of claim 27 wherein the neurons express tyrosine hydroxylase.

48. The method of claim 47 wherein the neurons are dopaminergic.