Abstract
Generalized status epilepticus (SE) triggers a robust neuroinflammatory response involving reactive astrocytosis, activation of brain-resident microglia, and brain infiltration of CCR2+ monocytes. Multiple lines of evidence indicate that quenching SE-induced neuroinflammation can alleviate the adverse consequences of SE, including neuronal damage and cognitive impairments. Our recent findings show that blocking monocyte brain entry after SE, via global Ccr2 KO, rescues several SE-induced adverse effects including blood-brain barrier (BBB) erosion, microgliosis and neuronal damage while enhancing weight regain. The goals of the present study were to determine if CCR2 antagonism with a small molecule after SE replicates the effects of the CCR2 knockout. Male Ccr2(+/rfp) heterozygous mice were subject to intraperitoneal injection of kainic acid, scored for seizure severity, weight recovery, and nest building capability. Surviving mice were randomized into CCR2 antagonist and vehicle groups. The CCR2 antagonist, or vehicle, was administered 24- and 48-h post-SE via oral gavage, and mice were sacrificed three days post-SE. Mice subject to the CCR2 antagonist displayed faster weight recovery between one- and three-days post-SE and modestly enhanced ability to build a nest on the third day after SE when compared to vehicle-treated controls. CCR2 antagonism limited monocyte recruitment to the hippocampus and reduced numbers of Iba1+ macrophages. The mRNA levels of inflammatory mediators were depressed by 47%, and glial markers were reduced by 30% in mice treated with the CCR2 antagonist compared to controls. Astrocytosis was reduced in four brain regions. Neuroprotection was observed in the hippocampus, and erosion of the BBB was lessened in mice subject to the antagonist. Our findings provide proof-of-concept that brief CCR2 antagonism beginning one day after SE can alleviate multiple adverse SE-induced effects, including functional impairment, and identify circulating CCR2+ monocytes as a viable therapeutic target.