Proteolytic Coherence and Trophic Divergence: Region-Specific Mapping of the tPA/PAI-1/uPAR and IGF/IGFBP-5 Responses to Kainic Acid-Induced Seizures.

Seizures trigger widespread molecular changes in the brain, but how these responses differ between surviving and degenerating regions remains unclear. Using the intrahippocampal kainic acid model, which is characterized by degeneration of the hippocampus, while the neocortex is less affected, we performed unbiased cytokine array screening and identified two functionally distinct systems that were prominently altered: the proteolytic tPA/PAI-1/uPAR axis and the trophic IGF/IGFBP-5 axis. Quantitative protein and mRNA analyses across five brain regions at 24 h post-seizures revealed distinct organizational patterns. The proteolytic axis showed a largely coordinated response: Serpine1 (PAI-1), Plat (tPA), and Plaur (uPAR) were coordinately upregulated across all studied structures, correlated with seizure severity, and showed minimal peripheral induction. The IGF system displayed a more region-dependent pattern, with Igfbp5 downregulation observed across all studied regions and divergent downstream trajectories. In the hippocampus, Igf2 and Igf1r were suppressed, consistent with reduced IGF signaling; in the neocortex, Igf1 and Igf1r were upregulated, mounting a compensatory response; the entorhinal cortex displayed an intermediate phenotype. Since IGFBP-5 may act as a co-activator of tPA and antagonist of PAI-1, its uniform downregulation together with the PAI-1 induction may create a coordinated shift that reduces proteolytic activity and alters IGF bioavailability across all regions. However, the neocortex appears to counteract this shift by upregulating Igf1 and Igf1r; the hippocampus does not, instead suppressing Igf2 and Igf1r. We propose that this region-specific coupling-between a universal proteolytic versus a trophic trigger and the capacity to mount a compensatory response-is one of the factors underlying the selective vulnerability of the hippocampus to seizure-induced neurodegeneration.