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MEADE, A.J., MELONI, B.P., CROSS, J., BAKKER, A.J., FEAR, M.W., MASTAGLIA, F.L., WATT, P.M. & KNUCKEY, N.W. (2010). AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures. Journal of Neurochemistry, 112(1), 258-270.
Title
AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures
Author
Year
2010
Published in
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.
Identifier
MEADE, A.J., MELONI, B.P., CROSS, J., BAKKER, A.J., FEAR, M.W., MASTAGLIA, F.L., WATT, P.M. & KNUCKEY, N.W. (2010). AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures. Journal of Neurochemistry, 112(1), 258-270.
Identifier
0022-3042
Identifier
http://repository.uwa.edu.au:80/R/-?func=dbin-jump-full&object_id=28566&silo_library=GEN01
ISBN/ISSN
0022-3042
Subject
Department/School
Type
Journal article
Additional Information
Link to Publisher's website supplied in Alternative Location.
Alternative Location
Persistent URL
http://repository.uwa.edu.au:80/R/-?func=dbin-jump-full&object_id=28566&silo_library=GEN01
Related collections
Medicine, Dentistry and Health Sciences > Paediatrics and Child Health