Attenuation of neuronal death by peptide inhibitors of AP-1 activation in acute and delayed in vitro ischaemia (oxygen/glucose deprivation) models

Using acute and delayed in vitro ischaemia models we evaluated the neuroprotective efficacy of five peptides (PYC19D-TAT, PYC35D-TAT, PYC36D-TAT, PYC38D-TAT, PYC41D-TAT) previously demonstrated to down-regulate AP-1 activation (e.g. c-Jun/c-Fos activation), and inhibit neuronal death in vitro following glutamate and kainic acid excitotoxicity. The JNK inhibitor peptide (JNKI-1D-TAT) and the TAT cell-penetrating-carrier peptide (D-TAT) were used as controls. In the acute model, all five AP-1 inhibitory peptides, JNKI-1D-TAT, and D-TAT provided neuroprotection by increasing neuronal viability from ≈5 to 23-53%. In the delayed model, three of the five AP-1 inhibitory peptides (PYC35D-TAT, PYC36D-TAT, PYC38D-TAT) and JNKI-1D-TAT provided neuroprotection by increasing neuronal viability from ≈10 to 35-80%. This study not only highlights a group of peptides with therapeutic potential, but also the need to assess putative therapeutics in multiple in vitro models to achieve a comprehensive representation of their neuroprotective capacity.