Treatment of Depressive Disorders
The invention provides for the use of carbonic anhydrase activators; protein kinase C activators and FGF-18 to treat depressive disorders. The invention also relates to improved animal models and methods for screening and identifying compounds the treatment of depressive disorders.
1 . A method comprising the steps of:
a) identifying a subject with a depressive disorder; and
b) administering an effective amount of a composition comprising a carbonic anhydrase activator and a pharmaceutically acceptable carrier to said subject, wherein the activator is selected from the group consisting of:
wherein R 1 is H or OH; R 2 and R 3 are independent H, COOH or lower alkyl, for example linear, branched or cyclic C 1 -C 6 alkyl or C 1 -C 4 alkyl; and Ar is phenyl, imidizolyl or phenyl or imidizolyl substituted with one or more halo, hydroxy, amino or lower alkyl groups for example linear, branched or cyclic C 1 -C 6 group or C 1 -C 4 alkyl group;
wherein R1 and R 2 are independently H or lower alkyl, for example linear, branched or cyclic C 1 -C 6 alkyl or C 1 -C 4 alkyl;
wherein n is 1 or 2 and R 2 is H or lower alkyl, for example linear, branched or cyclic C 1 -C 6 alkyl or C 1 -C 4 alkyl; and
pharmaceutically acceptable salts of I, II, or III.
2 . The method of claim 1 , wherein the activator has structure I wherein R 1 is H or OH; R 2 is H, CH 3 or COOH; R 3 is H or CH 3 ; and Ar is phenyl, or a substituted phenyl.
3 . The method of claim 2 , wherein the substituted phenyl is 4-hydroxyphenyl, 4-fluorophenyl, 4-aminophenyl, 3-amino-4-hydroxyphenyl, or 3,4-dihydroxyphenyl.
4 . The method of claim 1 , wherein the activator has structure I wherein R 1 is H or OH; R 2 is H, CH 3 or COOH; R 3 is H or CH 3 ; and Ar is imidazole or a substituted imidazole.
5 . The method of claim 4 , wherein the substituted imidazole is imadazol-4-yl-, or 5-methylimidazole-4-yl-.
6 . The method of claim 1 , wherein the activator has structure II wherein R 1 is H, methyl, ethyl or propyl; and R 2 is H or methyl.
7 . The method of claim 1 , wherein the activator is structure III wherein n is 1 or 2; and R 2 is H or methyl.
8 . The method of claim 1 , wherein the activator is selected from the group consisting of: imidazole, phenylalanine, a substituted ethylamine, phenethylamine, histamine, histidine, a linked di-imidazole, a triazole, and pharmaceutically acceptable salts thereof.
9 . The method of claim 8 , wherein the activator is histidine.
10 . The method of claim 8 , wherein the activator is histamine.
11 . The method of claim 8 , wherein the activator is phenylalanine.
12 . The method of claim 8 , wherein the activator is 4-hydroxy phenylalanine.
13 . The method of claim 8 , wherein the activator is 4-fluoro phenylalanine.
14 . The method of claim 8 , wherein the activator is 3,4-dihydroxy phenylalanine.
15 . The method of claim 8 , wherein the activator is 3-amino-4-hydroxyphenylalanine.
16 . The method of claim 8 , wherein the activator is 4-amino phenylalanine.
17 . The method of claim 8 , wherein the activator is tyrosine.
18 . The method of claim 8 , wherein the activator is dopamine.
19 . The method of claim 8 , wherein the activator is noradrenaline.
20 . The method of claim 8 , wherein the activator is adrenaline.
21 . The method of claim 8 , wherein the activator is histamine.
22 . The method of claim 8 , wherein the activator is 5-methyl histamine.
23 . A method of treating depression in a subject in need thereof, comprising administering an effective amount of a composition comprising a carbonic anhydrase activator and a pharmaceutically acceptable carrier, wherein the activator is selected from the group consisting of: an aromatic amine or an aromatic amino acid wherein the aromatic amine or aromatic amino acid contains a single aromatic group.
24 . The method of claim 23 , wherein the activator is selected from the group consisting of: phenylalanine, a substituted phenylalanine, histidine, a substituted histidine, a substituted phenylalanineimidazole, a substituted imidazole, a linked di-imidazole, and a linked substituted di-imidazole.
25 . The method of claim 1 , wherein the activator is an aromatic amine or an aromatic amino acid wherein the aromatic amine or aromatic amino acid contains a single aromatic group.
26 . The method of claim 25 , wherein the aromatic amine is selected from the group consisting of dopamine, noradrenaline, adrenaline, histamine, and 5-methyl histamine.
27 . The method of claim 23 , wherein the aromatic amine is selected from the group consisting of dopamine, noradrenaline, adrenaline, histamine, and 5-methyl histamine.
28 . The method of claim 1 , wherein the activator activates intraneuronal carbonic anhydrase.
29 . A method comprising the steps of:
a) identifying a subject with a depressive disorder; and
b) administering an effective amount of a composition comprising a protein kinase C activator and a pharmaceutically acceptable carrier to said subject, wherein the PKC activator is selected from a group consisting of: FGF-18, a macrocyclic lactone, a benzolactam, a pyrrolidinone, or a combination thereof.
30 . The method of claim 29 , wherein the macrocyclic lactone is a bryostatin or neristatin.
31 . The method of claim 30 , wherein the bryostatin is selected from a group consisting of bryostatin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.
32 . The method of claim 31 , wherein the bryostatin is bryostatin-1.
33 . The method of claim 30 , wherein the neristatin is neristatin-1.
34 . A method of treating depression in a subject in need thereof, comprising administering an effective amount of a composition comprising a protein kinase C activator and a pharmaceutically acceptable carrier, wherein the activator is selected from the group consisting of: FGF-18, a macrocyclic lactone, a benzolactam, a pyrrolidinone, or a combination thereof.
35 . The method of claim 34 , wherein the macrocyclic lactone is a bryostatin or neristatin.
36 . The method of claim 35 , wherein the bryostatin is selected from a group consisting of bryostatin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18.
37 . The method of claim 36 , wherein the bryostatin is bryostatin-1.
38 . The method of claim 35 , wherein the neristatin is neristatin-1.
39 . A method for screening an agent for antidepressant activity, comprising the steps of:
a) administering an agent in a pharmaceutically acceptable carrier to a test subject and administering the pharmaceutically acceptable carrier to the control subject;
b) individually placing said test and control subject into a pool of water and measuring the distance and/or duration of swimming during a testing period; and
c) comparing the distance or duration of swimming of the test subject to a control subject, wherein increased distance or duration of swimming of the test subject compared to the control subject is indicative of antidepressant activity.
40 . The method of claim 39 , wherein the pool is round.
41 . The method of claim 40 , wherein the pool has a diameter of between 100 and 200 cm.
42 . The method of claim 41 , wherein the pool has a diameter of 150 cm.
43 . The method of claim 39 , wherein the pool provides no escape.
44 . The method of claim 39 , wherein steps (a), (b), and (c) are repeated.
45 . The method of claim 44 , wherein the steps are repeated three times.
46 . The method of claim 39 , wherein the distance and/or duration of swimming is measured by video means.