THERAPEUTIC EFFECTS OF BRYOSTATINS, BRYOLOGS, AND OTHER RELATED SUBSTANCES ON ISCHEMIA/STROKE-INDUCED MEMORY IMPAIRMENT AND BRAIN INJURY
The invention provides for the use of protein kinase activators or boosters of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or other neurotrophic factors to treat stroke. Specifically, the present invention provides methods of treating stroke comprising the steps of identifying a subject having suffered a stroke and administering to said subject an amount of a pharmaceutical composition comprising a protein kinase C (PKC) activator or 4-methylcatechol acetic acid (MCBA) and a pharmaceutically acceptable carrier effective to treat at least one symptom of stroke.
1 - 19 . (canceled)
20 . A method of treating in a subject who has suffered an ischemic event, the method comprising administering to the subject an effective amount of a pharmaceutical composition sufficient to treat at least one symptom of stroke, wherein the composition comprises at least one protein kinase C (PKC) activator and a pharmaceutically acceptable carrier, and wherein the at least one PKC activator is chosen from bryologs, diacylglycerol derivatives other than phorbol esters, isoprenoids, daphnane-type diterpenes, bicyclic triterpenoids, naphthalenesulfonamides, linoleic acid derivatives, diacylglycerol kinase inhibitors, growth factor activators, and combinations thereof.
21 . The method of claim 20 , wherein the at least one PKC activator comprises a growth factor activator chosen from 4-methylcatechol derivatives.
22 . The method of claim 21 , wherein the 4-methylcatechol derivative is 4-methylcatechol acetic acid.
23 . The method of claim 20 , wherein administration of the pharmaceutical composition is initiated from 1 to 3 days after the ischemic event.
24 . The method of claim 20 , wherein the treatment is continued from 1 to 6 weeks.
25 . The method of claim 20 , wherein the treatment reverses stroke-induced brain injury.
26 . The method of claim 20 , wherein the treatment reverses stroke-induced memory impairment.
27 . The method of claim 20 , wherein the at least one PKC activator comprises a bryolog chosen from a B-ring bryolog and an A-ring bryolog.
28 . The method of claim 27 , wherein the bryolog has a molecular weight ranging from about 600 to 755 and an affinity for PKC ranging from about 0.25 nM to 10 μM.
29 . The method of claim 20 , wherein the at least one PKC activator comprises the bryolog
30 . The method of claim 20 , wherein the at least one PKC activator comprises the bryolog
31 . The method of claim 27 , wherein the B-ring byrolog is chosen from
and
32 . The method of claim 27 , wherein the A-ring bryolog is chosen from
wherein R is t-Bu, Ph, or (CH 2 ) 3 p-Br—Ph.
33 . The method of claim 20 , wherein the at least one PKC activator comprises a diacylglycerol derivative comprising unsaturated fatty acids.
34 . The method of claim 33 , wherein the fatty acids are in a 1,2-sn configuration.
35 . The method of claim 33 , wherein the fatty acids comprise cis-unsaturated fatty acids.
36 . The method of claim 20 , wherein the at least one PKC activator comprises octylindolactam V.
37 . The method of claim 36 , wherein the octylindolactam comprises the (−)-enantiomer.
38 . The method of claim 20 , wherein the at least one PKC activator comprises gnidimacrin.
39 . The method of claim 20 , wherein the at least one PKC activator comprises iripallidal.
40 . The method of claim 20 , wherein the at least one PKC activator comprises ingenol.
41 . The method of claim 20 , wherein the at least one PKC activator comprises ingenol 3,20-dibenzoate.
42 . The method of claim 20 , wherein the at least one PKC activator comprises ingenol-3-angelate.
43 . The method of claim 20 , wherein the at least one PKC activator comprises a napthalenesulfonamide chosen from N-(n-heptyl)-5-chloro-1-napthalenesulfonamide and N-(6-Phenylhexyl)-5-chloro-1-naphthalenesulfonamide.
44 . The method of claim 20 , wherein the at least one PKC activator comprises 2-[(2-pentylcyclopropyl)methyl]-cyclopropaneoctanoic acid.
45 . The method of claim 20 , wherein the at least one PKC activator comprises 6-(2-(4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl)ethyl)-7-methyl-5H-thiazolol[3,2-a]pyrimidin-5-one.
46 . The method of claim 20 , wherein the at least one PKC activator comprises [3-[2-[4-(bis-(4-fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone.