PGP and PGPL peptides exhibit distinct gene expression profiles compared to Semax in rat cerebral ischemia.

Cerebral ischemia-reperfusion, a hallmark of ischemic stroke, leads to significant brain damage, often involving complex inflammatory and neurosignaling cascades. Current neuroprotective strategies often fall short in fully mitigating this damage. Glyproline peptides, such as the synthetic Semax, which contains a Pro-Gly-Pro (PGP) tripeptide, have shown promise as neuroprotective agents by preventing gene expression disruption post-stroke. However, the specific mechanisms and comparative effects of other PGP-containing peptides on these critical gene clusters, particularly the inflammatory cluster (IC) and neurotransmitter cluster (NC), remain underexplored, presenting a gap in understanding their therapeutic potential.

Researchers investigated the effects of two PGP-containing peptides, Pro-Gly-Pro (PGP) and Pro-Gly-Pro-Leu (PGPL), on gene expression in a rat model of transient middle cerebral artery occlusion (tMCAO). The study focused on changes 24 hours after tMCAO, comparing the gene expression profiles of PGP and PGPL administration to those observed after Semax treatment under identical tMCAO conditions. Gene expression levels for specific genes within the inflammatory cluster (IC) and neurotransmitter cluster (NC) were quantified using real-time RT-PCR.

PGP and PGPL peptides demonstrated effects on gene expression that were distinct from those of Semax. While Semax previously showed a broad prevention of gene expression disruption 24 hours post-tMCAO, PGP and PGPL predominantly did not normalize overall gene expression. However, both peptides significantly altered specific gene levels when compared directly to Semax treatment. For PGP, significant changes were observed in IC genes, including iL1b, iL6, and Socs3. PGPL exhibited a broader impact, significantly altering IC genes such as iL6, Ccl3, Socs3, and Fos. Furthermore, PGPL also modulated NC genes, specifically Cplx2, Neurod6, and Ptk2b. Gene enrichment analysis and regulatory gene network construction further elucidated these unique and common effects. The most significant finding was that PGP and PGPL induced specific, Semax-unlike modulations in key inflammatory and neurosignaling genes, highlighting distinct mechanistic profiles for these glyproline peptides.