PDZ1 inhibitor peptide protects neurons against ischemia via inhibiting GluK2-PSD-95-module-mediated Fas signaling pathway

• Showed that PDZ1 inhibitor peptide effectively protected neuron against ischemia.
• Demonstrated that PDZ1 inhibitor peptide inhibited Fas pathway.
• Indicated that inhibitor peptides might be potential methods in stroke preservation.

Respecting the selective inhibition of peptides on protein–protein interactions, they might become potent methods in ischemic stroke therapy. In this study, we investigated the effect of PDZ1 inhibitor peptide on ischemic neuron apoptosis and the relative mechanism. Results showed that PDZ1 inhibitor peptide, which significantly disrupted GluK2-PSD-95 interaction, efficiently protected neuron from ischemia/reperfusion-induced apoptosis. Further, PDZ1 inhibited FasL expression, DISC assembly and activation of Caspase 8, Bid, Caspase 9 and Caspase 3 after global brain ischemia. Based on our previous report that GluK2-PSD-95 pathway increased FasL expression after global brain ischemia, the neuron protection effect of PDZ1 inhibitor peptide was considered to be achieved by disrupting GluK2-PSD-95 interaction and subsequently inhibiting FasL expression and Fas apoptosis pathway.