Pathological astroglial remodeling during epileptogenesis: the protective effect of losartan from cell culture to in vivo models

Pathological astroglial remodeling is a central event during epileptogenesis, contributing to the loss of glial homeostatic functions and neuronal hyperexcitability. In an in vitro astrocyte-enriched culture model, exposure to epileptogenic HMGB1 induced a reactive phenotype characterized by increased NFkB activation, DNA hypermethylation, reduced glutamine synthetase expression (GS), increased levels of the neurotoxic factor MAFG and proinflammatory cytokines. Losartan treatment (1-10 μM) consistently reversed these changes, restoring homeostatic genes GS, Kir4.1, GLT-1 and reducing MAFG and proinflammatory markers (IL-1β, IL-6). To validate these findings in vivo, the effect of losartan was evaluated in two animal models of epileptogenesis. In the hyperthermia seizure model (HS), losartan treatment (30 mg/kg/day) significantly reduced the GFAP+ immunoreactive area in both the hippocampal CA1 and the piriform cortex compared to the vehicle group. In the adult lithium-pilocarpine model of epilepsy, a significant decrease in GFAP+ area was also observed in both regions, and the expression of GS increased, suggesting a reduced reactive gliosis and restoration of the homeostatic astroglial phenotype. Taken together, these results show that epileptogenic astroglial remodeling in vitro and in vivo can be modulated by losartan, establishing itself as a promising therapeutic candidate to prevent epileptogenesis. Supported by grants: PICT 2021-0760, UBACYT, PIP CONICET