Inhibition of Astrocyte Reactivity by Mdivi-1 after Status Epilepticus in Rats Exacerbates Microglial-Mediated Neuroinflammation and Impairs Limbic-Cortical Glucose Metabolism

The lithium-pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset and we assessed brain glucose metabolism using [¹⁸F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by VOIs analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrocyte reactivity but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated cortical hypometabolism when evaluated by SPM normalized by whole brain tracer uptake and exacerbated microglial-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward a maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on early epileptogenic processes.