Region-Specific Long-Term Transcriptional Changes in the Plasminogen Activation System and Neuroinflammation in the...

Background/Objectives: Growing evidence implicates that processes mediated by cytokines, growth factors, and the plasminogen activation (PA) system play crucial roles in the pathogenesis of epilepsy and its comorbidities. Methods: This study was carried out on the lithium-pilocarpine rat model of status epilepticus (SE). We investigated mRNA expression patterns of PA system components (tPA/PAI-1/uPAR), pro-inflammatory cytokines (IL-1β/TNF-α), and TGF-β1 in the hippocampus and cortex 7 days (latent period) and 5 months (chronic period) after SE. In the chronic period, rats were subjected to the sucrose preference test for the evaluation of depressive-like behavior. Results: Our results revealed region-specific dysregulation of the PA system that persisted into the chronic period, with tPA (Plat) transiently upregulated in the dorsal hippocampus during the latent phase while uPAR (Plaur) exhibited sustained elevation in the entorhinal cortex into the chronic period. TGF-β1 (Tgfb1) exhibited widespread upregulation across all examined brain regions during the latent period, remaining elevated in the ventral hippocampus 5 months after SE. Notably, latent-phase neuroinflammation showed cortical specificity, with IL-1β (Il1b) expression increased in the frontal cortex while the hippocampal expression remained unchanged. The subgroup of rats displaying anhedonia (reduced sucrose preference) after SE exhibited higher Tgfb1 and Tnf expression in the ventral hippocampus and entorhinal cortex compared to non-anhedonic subgroup of rats and the control group (no SE) in the chronic period. Conclusions: Our findings demonstrate persistent, region-specific transcriptional changes in the PA system following SE, with higher expression of Tgfb1 and Tnf in a subgroup of rats with more severe functional outcome in the chronic period after SE.