Prevention of NMDA‐induced death of cortical neurons by inhibition of protein kinase Cζ

Koponen, Susanna; Kurkinen, Kaisa M.A.; Åkerman, Karl E.O.; Mochly‐Rosen, Daria; Chan, Pak H.; Koistinaho, Jari

doi:10.1046/j.1471-4159.2003.01846.x

Cited by 40 publications

(37 citation statements)

References 64 publications

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“…In a model of cardiac ischemia and reperfusion, we recently demonstrated a detrimental role for ␦PKC, promoting mitochondrial damage and induction of apoptosis (Inagaki et al, 2003b). Recent studies demonstrate that inhibition of PKC, but not ␦PKC, confers protection to neuron-astrocyte cultures exposed to a level of NMDA, which produced excitotoxic cell death (Koponen et al, 2003). The absence of protection conferred by the ␦PKC inhibitor may be attributable to the lack of apoptotic cell death in this model.…”

Section: ␦Pkc In Intracellular Injury Processesmentioning

confidence: 92%

Protein Kinase C δ Mediates Cerebral Reperfusion InjuryIn Vivo

Bright¹,

Raval²,

Dembner³

et al. 2004

J. Neurosci.

186

171

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Protein kinase C (PKC) has been implicated in mediating ischemic and reperfusion damage in multiple organs. However, conflicting reports exist on the role of individual PKC isozymes in cerebral ischemic injury. Using a peptide inhibitor selective for ␦PKC, ␦V1-1, we found that ␦PKC inhibition reduced cellular injury in a rat hippocampal slice model of cerebral ischemia [oxygen-glucose deprivation (OGD)] when present both during OGD and for the first 3 hr of reperfusion. We next demonstrated peptide delivery to the brain parenchyma after in vivo delivery by detecting biotin-conjugated ␦V1-1 and by measuring inhibition of intracellular ␦PKC translocation, an indicator of ␦PKC activity. Delivery of ␦V1-1 decreased infarct size in an in vivo rat stroke model of transient middle cerebral artery occlusion. Importantly, ␦V1-1 had no effect when delivered immediately before ischemia. However, delivery at the onset, at 1 hr, or at 6 hr of reperfusion reduced injury by 68, 47, and 58%, respectively. Previous work has implicated ␦PKC in mediating apoptotic processes. We therefore determined whether ␦PKC inhibition altered apoptotic cell death or cell survival pathways in our models. We found that ␦V1-1 reduced numbers of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells, indicating decreased apoptosis, increased levels of phospho-Akt, a kinase involved in cell survival pathways, and inhibited BAD (Bcl-2-associated death protein) protein translocation from the cell cytosol to the membrane, indicating inhibition of proapoptotic signaling. These data support a deleterious role for ␦PKC during reperfusion and suggest that ␦V1-1 delivery, even hours after commencement of reperfusion, may provide a therapeutic advantage after cerebral ischemia.

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Section: ␦Pkc In Intracellular Injury Processesmentioning

confidence: 92%

Protein Kinase C δ Mediates Cerebral Reperfusion InjuryIn Vivo

Bright¹,

Raval²,

Dembner³

et al. 2004

J. Neurosci.

186

171

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“…4 These events lead to rapid activation and increased expression of multiple PKC isozymes, as seen after glutamate, KCl or kainic acid application in vitro and in vivo. 50,68 -72 Correspondingly, PKC inhibition reduces NMDA-mediated neurotoxicity, 37,73,74 suggesting that PKC isozymes may mediate excitatory amino acid-induced signaling. ␥PKC is expressed exclusively in neurons of the brain and spinal cord.…”

Section: Ischemia and The Role Of Neuronal ␥Pkcmentioning

confidence: 99%

“…For example, PKC mediates NMDA-induced injury in primary neuronal cultures; inhibition of PKC reduces cellular damage, as monitored by LDH release. 74 A more detailed understanding of the molecular mechanism by which PKC elicits death in response to NMDA toxicity awaits further study.…”

Section: Ischemia and The Role Of Neuronal ␥Pkcmentioning

confidence: 99%

The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury

Bright

Mochly‐Rosen

2005

Stroke

186

141

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Background and Purpose-Stroke is a leading cause of disability and death in the United States, yet limited therapeutic options exist. The need for novel neuroprotective agents has spurred efforts to understand the intracellular signaling pathways that mediate cellular response to stroke. Protein kinase C (PKC) plays a central role in mediating ischemic and reperfusion damage in multiple tissues, including the brain. However, because of conflicting reports, it remains unclear whether PKC is involved in cell survival signaling, or mediates detrimental processes. Summary of Review-This review will examine the role of PKC activity in stroke. In particular, we will focus on more recent insights into the PKC isozyme-specific responses in neuronal preconditioning and in ischemia and reperfusioninduced stress. Conclusion-Examination of PKC isozyme activities during stroke demonstrates the clinical promise of PKC isozymespecific modulators for the treatment of cerebral ischemia.

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“…Calcium dependent PKC activity (A) and translocation (B) was assayed utilizing histone as substrate as described. 38 Calcium-independent PKC activity (C) and translocation (D) was assayed utilizing (Ser 25 ) PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] as substrate as described. 41 Translocation is reported as ratio of activity in membranes and soluble fractions after treatment with PMA 160 nM for 15 min.…”

Section: Kinase Activity Shows Strain and Substrate-dependent Changesmentioning

confidence: 99%

Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging

Battaini

2005

Annals of the New York Academy of Sciences

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Calcium/phospholipid-regulated protein kinase C (PKC) signalling is known to be involved in cellular functions relevant to brain health and disease, including ion channel modulation, receptor regulation, neurotransmitter release, synaptic plasticity, and survival. Brain aging is characterized by altered neuronal molecular cascades and interneuronal communication in response to various stimuli. In the last few years we have provided evidence that in rodents, despite no changes in PKC isoform levels (both calcium dependent and calcium independent), the activation/translocation process of the calcium-dependent and -independent kinases and the content of the adaptor protein RACK1 (receptor for activated C kinase-1) are deficient in physiological brain aging. Moreover, human studies have shown that PKC and its adaptor protein RACK1 are also interdependent in pathological brain aging (e.g., Alzheimer's disease); in fact, calcium-dependent PKC translocation and RACK1 levels are both deficient in an area-selective manner. These data point to the notion that, in addition to a well-described lipid environment alteration, changes in protein-protein interactions may impair the mechanisms of PKC activation in aging. It is interesting to note that interventions to counteract the age-related functional loss also restore PKC activation and the adaptor protein machinery expression. A better insight into the factors controlling PKC activation may be important not only to elucidate the molecular basis of signal transmission, but also to identify new strategies to correct or even to prevent agedependent alterations in cell-to-cell communication.

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Prevention of NMDA‐induced death of cortical neurons by inhibition of protein kinase Cζ

Cited by 40 publications

References 64 publications

Protein Kinase C δ Mediates Cerebral Reperfusion InjuryIn Vivo

Protein Kinase C δ Mediates Cerebral Reperfusion InjuryIn Vivo

The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury

Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging

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