AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures
Article first published online: 28 OCT 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 112, Issue 1, pages 258–270, January 2010
How to Cite
Meade, A. J., Meloni, B. P., Cross, J., Bakker, A. J., Fear, M. W., Mastaglia, F. L., Watt, P. M. and Knuckey, N. W. (2010), AP-1 inhibitory peptides are neuroprotective following acute glutamate excitotoxicity in primary cortical neuronal cultures. Journal of Neurochemistry, 112: 258–270. doi: 10.1111/j.1471-4159.2009.06459.x
- Issue published online: 8 DEC 2009
- Article first published online: 28 OCT 2009
- Received September 23, 2009; revised manuscript received October 14, 2009; accepted October 16, 2009.
Vol. 113, Issue 5, 1364, Article first published online: 14 APR 2010
- phylomer peptides;
J. Neurochem. (2010) 112, 258–270.
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.