Selective activation of protein kinase C∊ in mitochondria is neuroprotective in vitro and reduces focal ischemic brain injury in mice. Issue 6 (21st February 2013)

• Record Type: Journal Article
• Authors: Sun, Xiaoyun; Budas, Grant R.; Xu, Lijun; Barreto, George E.; Mochly‐Rosen, Daria; Giffard, Rona G.
• Is Part Of: Journal of neuroscience research. Volume 91:Issue 6(2013:Jun.)
• Page Start: 799
• Page End: 807
• Publication Date: 2013-02-21
• Subjects: Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.23186
• Languages: English
• ISSNs: 0360-4012

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 ∊V<sub>1–2</sub>, 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. © 2013 Wiley Periodicals, Inc.</p> </abstract>