title: Selective activation of protein kinase C∊ in mitochondria is neuroprotective in vitro and reduces focal ischemic brain injury in mice.
abstract: 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-Ψ∊RACK, or mitochondrial-selective PKC∊ activator, TAT-Ψ∊HSP90, reduced cell death induced by simulated ischemia/reperfusion in neurons, astrocytes, and mixed neuronal cultures. The protective effects of both TAT-Ψ∊RACK and TAT-Ψ∊HSP90 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-Ψ∊HSP90 was associated with a marked delay in mitochondrial membrane depolarization and significantly attenuated ROS generation during ischemia. Importantly, TAT-Ψ∊HSP90 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.
authors: Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, USA.
authors: Xiaoyun
authors: X
authors: Sun
authors: Grant R
authors: GR
authors: Budas
authors: Lijun
authors: L
authors: Xu
authors: George E
authors: GE
authors: Barreto
authors: Daria
authors: D
authors: Mochly-Rosen
authors: Rona G
authors: RG
authors: Giffard
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology; D020521:Stroke / Q000201:enzymology* / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species; D051744:Protein Kinase C-epsilon