CCR2 antagonism identifies blood-borne monocytes as a target for prevention of cognitive deficits after seizures

Abstract

Seizure-associated cognitive co-morbidities can substantially reduce the quality of life in people with epilepsy. Neuroinflammation is an invariant feature of all chronic neurologic diseases, including epilepsy, and acute brain insults, including status epilepticus (SE). The generalized seizures of SE trigger a robust inflammatory response involving astrocytosis, erosion of the blood-brain barrier (BBB), activation of brain-resident microglia, and recruitment of blood-borne CCR2+ monocytes into the brain. We have shown that blocking monocyte recruitment into the brain via global Ccr2 knockout or systemic CCR2 antagonism with a small molecule alleviates multiple deleterious SE-induced pathologies, including BBB damage, microgliosis, neuronal damage, and monocyte brain invasion in the days following pilocarpine-induced SE. This study aimed to determine if fleeting CCR2 antagonism improves SE-associated cognitive impairments in the long term. Here, we show that the brief antagonism of CCR2 eliminates the profound deficit in working memory in the Y-maze and retention memory in the novel object recognition test but does not attenuate anxiety-like behavior in the open field arena. Microgliosis and astrocytosis were observed in brain sections from SE mice after the behavioral tests, and CA1 hippocampal astrocytosis mildly correlated with performance in the Y-maze. Notably, SE mice exposed to the vehicle showed robust neuronal loss in the cortex and CA1 region of the hippocampus, and mice treated with the CCR2 antagonist showed less neurodegeneration in both the cortex and hippocampus. Our results indicate that monocyte brain infiltration after SE opens a window for preventing cognitive co-morbidities and neurodegeneration with an orally available CCR2 antagonist. HighlightsO_LICCR2 antagonism provides protection against seizure-associated cognitive deficits. C_LIO_LIA therapeutic window to alleviate SE-associated cognitive decline has been identified. C_LIO_LISelective immune modulation might be used to treat epilepsy co-morbidities. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/655010v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1f8060org.highwire.dtl.DTLVardef@25408aorg.highwire.dtl.DTLVardef@1b03589org.highwire.dtl.DTLVardef@18ad3fc_HPS_FORMAT_FIGEXP M_FIG C_FIG