Time-sequential Neuroinflammatory Response After Organophosphate-induced Status Epilepticus

Abstract

Background: Organophosphate compounds (OPs), either pesticides or chemical warfare agents are characterized by irreversible cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation leading to profound pathological alterations of the brain. The aim of this study was to characterize neuroinflammatory responses at key time points after DFP-induced SE.Methods: SE was induced by diisopropylfluorophosphate (DFP) injection in male Swiss mice. Immunohistochemistry (IHC) analyses of microglial (Iba1) and astrocytic (GFAP) cell markers were studied at 1, 4, 24 h and 3 days post-SE in the hippocampus. In parallel, using RT-qPCR, microglial and astrocytic phenotype markers were quantified on isolated CD11B (microglia) and GLAST (astrocytes)-positive cells after DFP-induced SE.Results: At earlier stages (1-4 h) after SE, although IHC analysis presented no modification, an increase in pro-inflammatory (M1-like) markers and A2-specific markers was observed in CD11B and GLAST-positive isolated cells respectively. Microglial cells sequentially expressed immuno-regulatory (M2b-like) and anti-inflammatory (M2a-like) at 4 h and 24 h of SE induction. At later stages (24 h and 3 days), microglial and astrocytic activations were visible by IHC and Iba1-positive cells were increased in number in DFP animals compared to controls. Finally, at these later stages, A1-specific markers were increased in isolated astrocytes.Conclusions: Our work identified sequential microglial and astrocytic phenotype activations. Although the role of each phenotype in SE cerebral consequences requires further study, targeting specific markers at specific time point could be a beneficial strategy for OP-induced SE treatment.