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Activating deltaPKC antagonizes the protective effect of ERK1/2 inhibition against stroke in rats.
- Source :
-
Brain research [Brain Res] 2009 Jan 28; Vol. 1251, pp. 256-61. Date of Electronic Publication: 2008 Nov 27. - Publication Year :
- 2009
-
Abstract
- Two pathways that have been shown to mediate cerebral ischemic damage are the MEK/ERK cascade and the pro-apoptotic deltaPKC pathway. We investigated the relationship between these pathways in a rat model of focal ischemia by observing and modifying the activation state of each pathway. The ERK1/2 inhibitor, U0126, injected at ischemia onset, attenuated the increase in phosphorylated ERK1/2 (P-ERK1/2) after reperfusion. The deltaPKC inhibitor, deltaV1-1, delivered at reperfusion, did not significantly change P-ERK1/2 levels. In contrast, the deltaPKC activator, psi deltaRACK, injected at reperfusion, reduced ERK1/2 phosphorylation measured 4 h after reperfusion. Additionally, U0126 pretreatment at ischemia onset reduced infarct size compared with vehicle, but U0126 injected at the onset of reperfusion had no protection. Finally, combination of U0126 injection at ischemia onset plus deltaV1-1 injection at reperfusion further reduced infarct size, while combination of U0126 delivered at ischemia onset with psi deltaRACK injected at reperfusion increased infarct size compared with U0126 alone. In conclusion, we find that inhibiting both the MEK/ERK and the deltaPKC pathways offers greater protection than either alone, indicating they likely act independently.
- Subjects :
- Animals
Brain Ischemia drug therapy
Brain Ischemia enzymology
Brain Ischemia physiopathology
Butadienes pharmacology
Disease Models, Animal
Drug Administration Schedule
Drug Therapy, Combination
Enzyme Inhibitors therapeutic use
Male
Mitogen-Activated Protein Kinase 3 antagonists & inhibitors
Neuroprotective Agents therapeutic use
Nitriles pharmacology
Phosphorylation drug effects
Protein Kinase C-delta antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Reperfusion Injury drug therapy
Reperfusion Injury enzymology
Reperfusion Injury metabolism
Reperfusion Injury physiopathology
Signal Transduction drug effects
Signal Transduction physiology
Stroke drug therapy
Stroke physiopathology
Up-Regulation drug effects
Up-Regulation physiology
Enzyme Inhibitors pharmacology
Mitogen-Activated Protein Kinase 3 metabolism
Neuroprotective Agents pharmacology
Protein Kinase C-delta metabolism
Stroke enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6240
- Volume :
- 1251
- Database :
- MEDLINE
- Journal :
- Brain research
- Publication Type :
- Academic Journal
- Accession number :
- 19063870
- Full Text :
- https://doi.org/10.1016/j.brainres.2008.11.051