PKC-activating compounds for the treatment of neurodegenerative diseases
View Patent ↗The present invention relates to methods of activate an isoform of protein kinase C (PKC) for the treatment of neurological diseases including Alzheimer's disease and stroke using cyclopropanated or epoxidized derivatives of mono- and polyunsaturated fatty acids. The present invention also relates to methods of reducing neurodegeneration using cyclopropanated or epoxidized derivatives of mono- and polyunsaturated fatty acids.
1. A method of activating an epsilon isoform of protein kinase C comprising contacting the epsilon isoform of protein kinase C with an effective amount of at least one compound chosen from a cis-polyunsaturated fatty acid ester in which at least one of the double bonds is replaced by a cyclopropyl group.
2. The method of claim 1 , wherein all of the double bonds are replaced by cyclopropyl groups.
3. The method of claim 1 , wherein the fatty acid from which the compound is derived has a structure of
CH 3 (CH 2 ) 4 (CH═CHCH 2 )x(CH 2 )yCOOH
or
CH 3 CH 2 (CH═CHCH 2 )x(CH2)yCOOH
wherein X is between 2 and 6 and Y is between 2 and 6.
4. The method of claim 1 , wherein the polyunsaturated fatty acid from which the compound is derived is chosen from arachidonic acid, docosapentaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid, γ-linoleic acid, α-linolenic acid, eicosatetraenoic acid, adrenic acid, and derivatives thereof.
5. The method of claim 1 , wherein the compound is chosen from cyclopropanated docosahexaenoic acid methyl ester (BR-111), cyclopropanated eicosapentaenoic acid methyl ester (BR-114), and cyclopropanated arachidonic acid methyl ester (BR-115).
6. The method of claim 1 , wherein the ester is a fatty acid alcohol ester.
7. The method of claim 6 , wherein the alcohol is an aliphatic alcohol.
8. The method of claim 7 , wherein the aliphatic alcohol is glycerol.
9. The method of claim 1 , wherein the effective amount of the compound is between about 5 nanomolar to about 10 micromolar.
10. The method of claim 1 ,
wherein the compound activates the epsilon isoform of protein kinase C at least 2-fold over the alpha isoform of protein kinase C or over an epsilon isoform of protein kinase C not contacted with the compound.
11. A method for reducing neurodegeneration comprising administering to a subject in need thereof an effective amount of at least one compound chosen from a cis-polyunsaturated fatty acid ester in which at least one of the double bonds is replaced by a cyclopropyl group.
12. The method of claim 11 , wherein all of the double bonds are replaced by cyclopropyl groups.
13. The method of claim 11 , wherein the fatty acid from which the compound is derived has a structure of
CH 3 (CH 2 ) 4 (CH═CH CH 2 )x(CH 2 )yCOOH
or
CH 3 CH 2 (CH═CHCH 2 )x(CH 2 )yCOOH
wherein X is between 2 and 6 and Y is between 2 and 6.
14. The method of claim 11 , wherein the polyunsaturated fatty acid from which the compound is derived is chosen from arachidonic acid, docosapentaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid, γ-linoleic acid, α-linolenic acid, eicosatetraenoic acid, adrenic acid, and derivatives thereof.
15. The method of claim 11 , wherein the compound is chosen from cyclopropanated docosahexaenoicacid methyl ester (BR-111), cyclopropanated eicosapentaenoic acid methyl ester (BR-114), and cyclopropanated arachidonic acid methyl ester (BR-115).