Amanda J. Meade, Bruno P. Meloni, Frank L. Mastaglia, Paul M. Watt, Neville W. Knuckey

This study has assessed the neuroprotective efficacy of five AP-1 inhibitory peptides in an in vitro excitotoxicity model. The five AP-1 inhibitory peptides and controls of the JNK inhibitor peptide (JNKI-1D-TAT) and TAT cell-penetrating-peptide were administered to primary cortical neuronal cultures prior to kainic acid exposure. All five AP-1 inhibitory peptides and JNKI-1D-TAT provided significant neuroprotection from kainic acid induced neuronal cell death. Kainic acid exposure induced caspase and calpain activation in neuronal cultures, with caspase-induced cleavage of α-fodrin reduced by administration of the AP-1 inhibitory peptides. Sequence analysis of the AP-1 inhibitory peptides did not reveal the presence of any secondary structures; however two peptides shared 66% amino-acid sequence homology. As a result, truncated sequences were designed and synthesised to identify the active region of the peptides. All truncated peptides were significantly neuroprotective following kainic acid and glutamate exposure. We have shown for the first time the neuroprotective efficacy of full-length and truncated AP-1 inhibitory peptides in kainic acid and glutamate neuronal excitotoxicity models. The identification of therapeutic targets, such as the AP-1 complex, is an important step for the development of pharmaceuticals to reduce neuronal loss in disorders with a prevalence of excitotoxic cell death such as epilepsy, cerebral ischaemia, and traumatic brain injury.