Claims
- 1. A method of treating a subject in need of treatment of a neurodegenerative disease, said method comprising administering to said subject a pharmaceutically effective amount of a compound that elevates intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme in diseased tissue of said subject.
- 2. The method of claim 1, wherein said compound is selected from the group consisting of a glutathione precursor, an isothiocyanate and a glucosinolate.
- 3. The method of claim 2, wherein said isothiocyanate is selected from the group consisting of sulforaphane and a sulforaphane analog.
- 4. The method of claim 3, wherein said sulforaphane analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis-3(methylsulfonyl)cyclohexylmethylisothiocyanate and trans-3(methylsulfonyl)cyclohexylmethylisothiocyanate.
- 5. The method of claim 1, wherein said compound is selected from the group consisting of resveratrol, oltipraz, dimethylfumarate, 2(3)tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxytoluene and an analog thereof.
- 6. The method of claim 1, wherein said neurological disorder is selected from the group consisting Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, epilepsy, myasthenia gravis, neuropathy, ataxia, dementia, chronic axonal neuropathy and stroke.
- 7. The method of claim 1 wherein said Phase II detoxification enzyme is selected from the group consisting of UDP-glucuronosyltransferases, sulfotransferases, phenol-O-methyltransferase, catechol-O-methyltransferase, histamine N-methyltransferase, nicotinamide N-methyltransferase, thiopurine methyltransferase, thiol methyltransferase, N-acetyltransferases, O-acetyltransferases, acyl-CoA synthetases, acyl-CoA:amino acid N-acyltransferases, aminoacyl-tRNA synthetases, glutathione synthetases, gamma glutamylcysteine synthetases, glutathione S-transferases, quinone reductases, heme oxygenases, rhodaneses, glutathione reductase, glutathione peroxidase, catalase and superoxide dismutase.
- 8. A method of inhibiting cell death in neuronal cells comprising treating said neuronal cells with an agent that increases intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme.
- 9. The method of claim 8, wherein said agent is selected from the group consisting of a glutathione precursor, an isothiocyanate and a glucosinolate.
- 10. The method of claim 9, wherein said isothiocyanate is selected from the group consisting of sulforaphane and a sulforaphane analog.
- 11. The method of claim 10, wherein said sulforaphane analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis-3(methylsulfonyl)cyclohexylmethylisothiocyanate and trans-3(methylsulfonyl)cyclohexylmethylisothiocyanate.
- 12. The method of claim 8, wherein said compound is selected from the group consisting of resveratrol, oltipraz, dimethylfumarate, 2(3)tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxytoluene and an analog thereof.
- 13. The method of claim 8, wherein said Phase II detoxification enzyme is selected from the group consisting of UDP-glucuronosyltransferases, sulfotransferases, phenol-O-methyltransferase, catechol-O-methyltransferase, histamine N-methyltransferase, nicotinamide N-methyltransferase, thiopurine methyltransferase, thiol methyltransferase, N-acetyltransferases, O-acetyltransferases, acyl-CoA synthetases, acyl-CoA:amino acid N-acyltransferases, aminoacyl-tRNA synthetases, glutathione synthetases, gamma glutamylcysteine synthetases, glutathione S-transferases, quinone reductases, heme oxygenases rhodaneses, glutathione reductase, glutathione peroxidase, catalase and superoxide dismutase.
- 14. A method of identifying agents that modulate intracellular levels of glutathione or intracellular levels of at least one Phase II enzyme in neuronal cells comprising
a. treating said neuronal cells with an agent, and assaying for intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme; b. treating said neuronal cells with a known modulator of intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme, and assaying for intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme; c. comparing the levels of said intracellular glutathione or intracellular levels of at least one Phase II detoxification enzyme in (a) and (b) to determine if said agent modulates intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme.
- 15. The method of claim 14, wherein (b) is performed on said neuronal cells of (a) after said agent in (a) is removed.
- 16. The method of claim 14, wherein said known modulator of intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme increases intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme.
- 17. The method of claim 14 wherein said known modulator of intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme decreases intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme.
- 18. The method of claim 14, wherein said known modulator of intracellular levels of glutathione or intracellular levels of at least one Phase II detoxification enzyme is selected from the group consisting of an isothiocyanate, a glutathione precursor and a glucosinolate.
- 19. The method of claim 18, wherein said isothiocyanate is selected from the group consisting of sulforaphane and a sulforaphane analog.
- 20. The method of claim 19, wherein said sulforaphane analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis-3(methylsulfonyl)cyclohexylmethylisothiocyanate and trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate.
- 21. A method of modulating intracellular levels of at least one Phase II detoxification enzyme in neuronal cells, said method comprising treating said neuronal cells with an agent that binds to glutathione to form a complex, wherein said complex modulates said intracellular levels of at least one Phase II detoxification enzyme.
- 22. The method of claim 21, wherein said agent is selected from the group consisting of a glutathione precursor, an isothiocyanate and a glucosinolate.
- 23. The method of claim 22, wherein said isothiocyanate is selected from the group consisting of sulforaphane and a sulforaphane analog.
- 24. The method of claim 23, wherein said sulforaphane analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis-3(methylsulfonyl)cyclohexylmethylisothiocyanate and trans-3(methylsulfonyl)cyclohexylmethylisothiocyanate.
- 25. The method of claim 21, wherein said compound is selected from the group consisting of resveratrol, oltipraz, dimethylfumarate, 2(3)tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxytoluene and an analog thereof.
- 26. The method of claim 21, wherein said Phase II detoxification enzyme is selected from the group consisting of UDP-glucuronosyltransferases, sulfotransferases, phenol-O-methyltransferase, catechol-O-methyltransferase, histamine N-methyltransferase, nicotinamide N-methyltransferase, thiopurine methyltransferase, thiol methyltransferase, N-acetyltransferases, O-acetyltransferases, acyl-CoA synthetases, acyl-CoA:amino acid N-acyltransferases, aminoacyl-tRNA synthetases, glutathione synthetases, gamma glutamylcysteine synthetases, glutathione S-transferases, quinone reductases, and heme oxygenases rhodaneses, glutathione reductase, glutathione peroxidase, catalase and superoxide dismutase.
- 27. A composition for use in the treatment of a degenerative disease, comprising a pharmaceutical excipient and a pharmaceutically effective amount of an agent that increases intracellular levels of glutathione or at least one Phase II detoxification enzyme.
- 28. The composition of claim 27, wherein said agent is selected from the group consisting of a glutathione precursor, an isothiocyanate and a glucosinolate.
- 29. The composition of claim 28, wherein said isothiocyanate is selected from the group consisting of sulforaphane and a sulforaphane analog.
- 30. The composition of claim 29, wherein said sulforaphane analog is selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6-isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonylnorbornane, 6-isothiocyanato-2-hexanol, 1-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(1′-hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1-isothiocyanato-5-methylsulfonylpentane, cis-3(methylsulfonyl)cyclohexylmethylisothiocyanate and trans-3-(methylsulfonyl)cyclohexylmethylisothiocyanate.
- 31. The composition of claim 27, wherein said agent is selected from the group consisting of resveratrol, oltipraz, dimethylfumarate, 2(3)-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxytoluene and an analog thereof.
- 32. The composition of claim 27, wherein said neurological disorder is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, epilepsy, myasthenia gravis, neuropathy, ataxia, dementia, chronic axonal neuropathy and stroke.
- 33. The composition of claim 27 wherein said Phase II detoxification enzyme is selected from the group consisting of UDP-glucuronosyltransferases, sulfotransferases, phenol-O-methyltransferase, catechol-O-methyltransferase, histamine N-methyltransferase, nicotinamide N-methyltransferase, thiopurine methyltransferase, thiol methyltransferase, N-acetyltransferases, O-acetyltransferases, acyl-CoA synthetases, acyl-CoA:amino acid N-acyltransferases, aminoacyl-tRNA synthetases, glutathione synthetases, gamma glutamylcysteine synthetases, glutathione S-transferases, quinone reductases, heme oxygenases, rhodaneses, glutathione reductase, glutathione peroxidase, catalase and superoxide dismutase.
STATEMENT AS TO THE RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0001] Part of the work performed during development of this invention utilized U.S. Government funds. The U.S. Government has certain rights in this invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60215812 |
Jul 2000 |
US |