Post-ischemic activation of protein kinase C epsilon protects the hippocampus from cerebral ischemic injury via alterations in cerebral blood flow

Della-Morte, David; Raval, Ami P.; Dave, Kunjan R.; Lin, Hung Wen; Pérez-Pinzón, Miguel A.

doi:10.1016/j.neulet.2010.10.013

Cited by 40 publications

(44 citation statements)

References 22 publications

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“…[28][29][30] Both PKCe and AMPK have established roles in ischemic neuroprotection and enhancing mitochondrial function. For example, our previous studies in the brain showed that PKCe mediates ischemic protection 25 and translocates to mitochondria where it regulates the mitochondrial K þ ATP channel, 26 increases mitochondrial respiration, decreases reactive oxygen species production, and inhibits cytochrome c release. 9 While PKCe has an established role in preventing brain ischemic injury, the role of AMPK in ischemic protection in the brain is less clear.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Morris-Blanco

Cohan

Neumann

et al. 2014

J Cereb Blood Flow Metab

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Preserving mitochondrial pools of nicotinamide adenine dinucleotide (NAD) or nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in NAD production, maintains mitochondrial function and confers neuroprotection after ischemic stress. However, the mechanisms involved in regulating mitochondrial-localized Nampt or NAD have not been defined. In this study, we investigated the roles of protein kinase C epsilon (PKCe) and AMP-activated protein kinase (AMPK) in regulating mitochondrial pools of Nampt and NAD after resveratrol or ischemic preconditioning (IPC) in the cortex and in primary neuronal-glial cortical cultures. Using the specific PKCe agonist ceRACK, we found that PKCe induced robust activation of AMPK in vitro and in vivo and that AMPK was required for PKCe-mediated ischemic neuroprotection. In purified mitochondrial fractions, PKCe enhanced Nampt levels in an AMPK-dependent manner and was required for increased mitochondrial Nampt after IPC or resveratrol treatment. Analysis of intrinsic NAD autofluorescence using two-photon microscopy revealed that PKCe modulated NAD in the mitochondrial fraction. Further assessments of mitochondrial NAD concentrations showed that PKCe has a key role in regulating the mitochondrial NAD þ / nicotinamide adenine dinucleotide reduced (NADH) ratio after IPC and resveratrol treatment in an AMPK-and Nampt-dependent manner. These findings indicate that PKCe is critical to increase or maintain mitochondrial Nampt and NAD after pathways of ischemic neuroprotection in the brain.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Morris-Blanco

Cohan

Neumann

et al. 2014

J Cereb Blood Flow Metab

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“…Recent studies suggest that PKCepsilon might confer protection against ischemic injury by decreasing post-ischemic cerebral blood fl ow [ 110 ] .…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

The Biology of Protein Kinase C

Zeng

Webster

Newton

2012

Advances in Experimental Medicine and Biology

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This review gives a basic introduction to the biology of protein kinase C, one of the first calcium-dependent kinases to be discovered. We review the structure and function of protein kinase C, along with some of the substrates of individual isoforms. We then review strategies for inhibiting PKC in experimental systems and finally discuss the therapeutic potential of targeting PKC. Each aspect is covered in summary, with links to detailed resources where appropriate.

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“…TAT--RACK fusion protein iv Rat, Global cerebral ischemia Activation of PKC by TAT--RACK protects the brain against ischemic damage by regulating cerebral blood flow [114] c-Jun N-terminal kinase-inhibitor (D-JNKI1) TAT-DJNKI1 fusion protein ip Rat/mouse, permanent ischemia JNK inhibitor; reduces lesion volume and improves neurological function [115][116][117] JNK-inhibitor JBD TAT-JBD fusion protein ip…”

Section: V1-1-tat Fusion Protein Ipmentioning

confidence: 99%

“…In contrast to PKC, the activation of PKC, a different member of the PKC family, was documented to be neuroprotective against cerebral ischemia [113,114]. Intravenous pretreatment with a fusion protein of TAT--Receptors for Activated C Kinase (RACK), a PKC-selective peptide activator, 30 min prior to global cerebral ischemia conferred protection to the CA1 region of the rat hippocampus by regulating cerebral blood flow [114].…”

Section: Protein Kinasesmentioning

confidence: 99%

See 1 more Smart Citation

Delivery of Neurotherapeutics Across the Blood Brain Barrier in Stroke

Hu¹,

Zhang²,

Leak³

et al. 2012

curr pharm des

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Stroke is a devastating disease with few therapeutic options. Despite our growing understanding of the critical mechanistic events in post-stroke brain injury, the clinical translation of these findings has been less effective. A monumental hurdle to the field has been the inability of many systemically applied therapies to efficiently cross the blood brain barrier (BBB) and enter brain cells. Over the last two decades, however, significant technological achievements have overcome this obstacle to facilitate central nervous system (CNS) drug delivery. Noninvasive drug carriers, especially cell penetrating peptide (CPP) show great potential to deliver neurotherapeutics across the BBB for the treatment of ischemic brain injury. This review begins with a brief introduction to the BBB in relation to drug delivery and then provides an overview of the development of drug carriers for neurotherapeutics, with a focus on CPP-mediated transduction. We discuss recent advances and limitations in this field, as well as mechanisms underlying CPP-mediated brain targeting. We also summarize the application of CPPs in stroke research. Continuing modifications and improvements of CPPs are expected to enhance both their feasibility in clinical stroke management and their specificity towards particular cell types.

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Post-ischemic activation of protein kinase C epsilon protects the hippocampus from cerebral ischemic injury via alterations in cerebral blood flow

Cited by 40 publications

References 22 publications

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

The Biology of Protein Kinase C

Delivery of Neurotherapeutics Across the Blood Brain Barrier in Stroke

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