Journal article
AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures
Journal of Neurochemistry, Vol.112(1), pp.258-270
2010
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.
Details
- Title
- AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures
- Authors/Creators
- A.J. Meade (Author/Creator)B.P. Meloni (Author/Creator)J. Cross (Author/Creator)A.J. Bakker (Author/Creator)M.W. Fear (Author/Creator)F.L. Mastaglia (Author/Creator)P.M. Watt (Author/Creator)N.W. Knuckey (Author/Creator)
- Publication Details
- Journal of Neurochemistry, Vol.112(1), pp.258-270
- Publisher
- Wiley
- Identifiers
- 991005542153207891
- Copyright
- © 2009 The Authors.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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