AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures

Authors

  • Amanda J. Meade,

    1. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia and Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, WA, Australia
    2. Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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  • Bruno P. Meloni,

    1. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia and Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, WA, Australia
    2. Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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  • Jane Cross,

    1. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia and Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, WA, Australia
    2. Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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  • Anthony J. Bakker,

    1. School Biomedical and Chemical Sciences, The University of Western Australia
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  • Mark W. Fear,

    1. McComb Foundation, WA, Australia
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  • Frank L. Mastaglia,

    1. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia and Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, WA, Australia
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  • Paul M. Watt,

    1. Phylogica Ltd and Telethon Institute for Child Health Research, The University of Western Australia, Australia
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  • Neville W. Knuckey

    1. Centre for Neuromuscular and Neurological Disorders, The University of Western Australia and Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, WA, Australia
    2. Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
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Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 113, Issue 5, 1364, Article first published online: 14 April 2010

Address correspondence and reprint requests to Amanda Meade, Australian Neuromuscular Research Institute, A Block, 4th Floor, QEII Medical Centre, Verdun St, Nedlands WA 6009, Australia. E-mail: meadea01@student.uwa.edu.au

Abstract

J. Neurochem. (2010) 112, 258–270.

Abstract

Neuronal cell death caused by glutamate excitotoxicity is prevalent in various neurological disorders and has been associated with the transcriptional activation of activator protein-1 (AP-1). In this study, we tested 19 recently isolated AP-1 inhibitory peptides, fused to the cell penetrating peptide TAT, for their efficacy in preventing cell death in cortical neuronal cultures following glutamate excitotoxicity. Five peptides (PYC19D-TAT, PYC35D-TAT, PYC36D-TAT, PYC38D-TAT, PYC41D-TAT) displayed neuroprotective activity in concentration responses in both l- and retro-inverso d-isoforms with increasing levels of neuroprotection peaking at 83%. Interestingly, the D-TAT peptide displayed a neuroprotective effect increasing neuronal survival to 25%. Using an AP-1 luciferase reporter assay, we confirmed that the AP-1 inhibitory peptides reduce AP-1 transcriptional activation, and that c-Jun and c-Fos mRNA following glutamate exposure is reduced. In addition, following glutamate exposure the AP-1 inhibitory peptides decreased calpain-mediated α-fodrin cleavage, but not neuronal calcium influx. Finally, as neuronal death following glutamate excitotoxicity was transcriptionally independent (actinomycin D insensitive), our data indicate that activation of AP-1 proteins can induce cell death via non-transcriptional pathways. Thus, these peptides have potential application as therapeutics directly or for the rational design of small molecule inhibitors in both apoptotic and necrotic neuronal death associated with AP-1 activation.

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