PKC activators and anticoagulant in regimen for treating stroke
The present disclosure provides a method for treating stroke by administering to a subject an anticoagulant, e.g., recombinant tissue plasminogen activator (rTPA), and a protein kinase C (PKC) activator followed by administration of at least one PKC activator for a duration of treatment. The methods disclosed herein may limit the size of infarction and/or reduce mortality, the disruption of the blood-brain barrier, and/or the hemorrhagic damage due to ischemic stroke compared with rTPA administration alone; and may also extend the therapeutic time window for administering rTPA after a stroke. Also disclosed are kits comprising rTPA and a PKC activator for treating stroke.
1. A method of treating a subject who has suffered an ischemic event comprising:
(a) administering to the subject an anticoagulant and a protein kinase C (PKC) activator within about 24 hours after the ischemic event, wherein the anticoagulant is administered before the PKC activator; and
(b) administering at least one PKC activator after step (a) for a duration of treatment;
wherein the PKC activators of step (a) and step (b) are the same or different.
2. The method of claim 1 , wherein the anticoagulant is tissue plasminogen activator (TPA).
3. The method of claim 1 , wherein the PKC activators of step (a) and step (b) each independently bind to at least one of the 1,2-diacylglycerol (DAG) and 1,2-diacyl-sn-glycero-3-phospho-L-serine (phosphatidyl-L-serine, PS) sites of PKC, or indirectly activate PKC.
4. The method of claim 1 , wherein the PKC activators of step (a) and step (b) are each independently chosen from macrocyclic lactones, diacylglycerol derivatives other than phorbol esters, isoprenoids, daphnane-type diterpenes, bicyclic triterpenoids, naphthalenesulfonamides, diacylglycerol kinase inhibitors, growth factor activators, and fatty acids and derivatives thereof.
5. The method of claim 4 , wherein the macrocyclic lactones are chosen from bryostatin, bryologs, and neristatin.
6. The method of claim 5 , wherein the bryostatin is bryostatin-1.
7. The method of claim 1 , wherein in step (a) the anticoagulant is administered within 24 hours after the ischemic event.
8. The method of claim 7 , wherein in step (a) the anticoagulant is administered from about 1 hour to about 12 hours after the ischemic event.
9. The method of claim 8 , wherein in step (a) the anticoagulant is administered from about 2 hours to about 6 hours after the ischemic event.
10. The method of claim 1 , wherein in step (a) the PKC activator is administered within 24 hours after administration of the anticoagulant.
11. The method of claim 10 , wherein in step (a) the PKC activator is administered from about 1 hour to about 12 hours after administration of the anticoagulant.
12. The method of claim 11 , wherein in step (a) the PKC activator is administered from about 2 hours to about 6 hours after the anticoagulant.
13. The method of claim 1 , wherein in step (a) the anticoagulant is administered within about 6 hours after the ischemic event and the PKC activator is administered within about 2 hours after the anticoagulant.
14. The method of claim 13 , wherein in step (a) the anticoagulant is administered about 3 hours after the ischemic event and the PKC activator is administered about 2 hours after the anticoagulant.
15. The method of claim 1 , wherein the treatment in step (b) is initiated from about 10 hours to about 32 hours after the ischemic event.
16. The method of claim 15 , wherein the treatment of step (b) is initiated about 24 hours after the ischemic event.
17. The method of claim 1 , wherein in step (b) the PKC activator is administered from 1-3 times per week.
18. The method of claim 1 , wherein the duration of treatment in step (b) ranges from about 1 week to about 10 weeks.
19. The method of claim 1 , wherein in step (b) the PKC activator is administered by intravenous injection.
20. The method of claim 1 , wherein mortality is reduced compared to administration of the anticoagulant alone.
21. The method of claim 20 , wherein mortality 24 hours after the stroke is reduced by at least 40%.
22. The method of claim 1 , wherein hemorrhagic transformation is reduced compared to administration of the anticoagulant alone.
23. The method of claim 22 , wherein the reduction in hemorrhagic transformation is determined by measuring the subject's hemoglobin level compared to administration of the anticoagulant alone.
24. The method of claim 23 , wherein the hemoglobin level is reduced by about 50%.
25. The method of claim 1 , wherein disruption of the blood-brain barrier is reduced compared to administration of the anticoagulant alone.
26. The method of claim 1 , wherein the treatment reverses stroke-induced brain injury.
27. The method of claim 1 , wherein the treatment reverses stroke-induced memory impairment.