Peer-Reviewed Journal Details
Mandatory Fields
Sun, X.,Budas, G. R.,Xu, L.,Barreto, G. E.,Mochly-Rosen, D.,Giffard, R. G.
2013
June
J Neurosci Resj Neurosci Res
Selective activation of protein kinase C in mitochondria is neuroprotective in vitro and reduces focal ischemic brain injury in mice
Published
()
Optional Fields
Animals Blotting, Western Brain Ischemia/*enzymology/pathology Cerebrovascular Circulation/physiology Enzyme Activation/physiology Membrane Potential, Mitochondrial Mice Mitochondria/*enzymology Protein Kinase C-epsilon/*metabolism Reactive Oxygen Species/metabolism Reperfusion Injury/enzymology/pathology Stroke/*enzymology/pathology
91
66
799
807
Activation of protein kinase C (PKC) confers protection against neuronal ischemia/reperfusion. Activation of PKC leads to its translocation to multiple intracellular sites, so a mitochondria-selective PKC activator was used to test the importance of mitochondrial activation to the neuroprotective effect of PKC. PKC can regulate key cytoprotective mitochondrial functions, including electron transport chain activity, reactive oxygen species (ROS) generation, mitochondrial permeability transition, and detoxification of reactive aldehydes. We tested the ability of mitochondria-selective activation of PKC to protect primary brain cell cultures or mice subjected to ischemic stroke. Pretreatment with either general PKC activator peptide, TAT-PsiRACK, or mitochondrial-selective PKC activator, TAT-PsiHSP90, reduced cell death induced by simulated ischemia/reperfusion in neurons, astrocytes, and mixed neuronal cultures. The protective effects of both TAT-PsiRACK and TAT-PsiHSP90 were blocked by the PKC antagonist V1-2 , indicating that protection requires PKC interaction with its anchoring protein, TAT-RACK. Further supporting a mitochondrial mechanism for PKC, neuroprotection by TAT-PsiHSP90 was associated with a marked delay in mitochondrial membrane depolarization and significantly attenuated ROS generation during ischemia. Importantly, TAT-PsiHSP90 reduced infarct size and reduced neurological deficit in C57/BL6 mice subjected to middle cerebral artery occlusion and 24 hr of reperfusion. Thus selective activation of mitochondrial PKC preserves mitochondrial function in vitro and improves outcome in vivo, suggesting potential therapeutic value clinically when brain ischemia is anticipated, including neurosurgery and cardiac surgery.Activation of protein kinase C (PKC) confers protection against neuronal ischemia/reperfusion. Activation of PKC leads to its translocation to multiple intracellular sites, so a mitochondria-selective PKC activator was used to test the importance of mitochondrial activation to the neuroprotective effect of PKC. PKC can regulate key cytoprotective mitochondrial functions, including electron transport chain activity, reactive oxygen species (ROS) generation, mitochondrial permeability transition, and detoxification of reactive aldehydes. We tested the ability of mitochondria-selective activation of PKC to protect primary brain cell cultures or mice subjected to ischemic stroke. Pretreatment with either general PKC activator peptide, TAT-PsiRACK, or mitochondrial-selective PKC activator, TAT-PsiHSP90, reduced cell death induced by simulated ischemia/reperfusion in neurons, astrocytes, and mixed neuronal cultures. The protective effects of both TAT-PsiRACK and TAT-PsiHSP90 were blocked by the PKC antagonist V1-2 , indicating that protection requires PKC interaction with its anchoring protein, TAT-RACK. Further supporting a mitochondrial mechanism for PKC, neuroprotection by TAT-PsiHSP90 was associated with a marked delay in mitochondrial membrane depolarization and significantly attenuated ROS generation during ischemia. Importantly, TAT-PsiHSP90 reduced infarct size and reduced neurological deficit in C57/BL6 mice subjected to middle cerebral artery occlusion and 24 hr of reperfusion. Thus selective activation of mitochondrial PKC preserves mitochondrial function in vitro and improves outcome in vivo, suggesting potential therapeutic value clinically when brain ischemia is anticipated, including neurosurgery and cardiac surgery.
1097-4547 (Electronic) 03
2013/02/22
http://www.ncbi.nlm.nih.gov/pubmed/23426889http://www.ncbi.nlm.nih.gov/pubmed/23426889
10.1002/jnr.23186
Grant Details