Abstracts

Rationale: Although epilepsy is known as a disease of seizures, many people with epilepsy also suffer from seizure-associated cognitive comorbidities that degrade quality of life. Neuroinflammation is an invariant feature of chronic neurologic disease, including epilepsy, and acute insults such as status epilepticus (SE). Our previous work has demonstrated neuroinflammatory gene induction within 30 minutes of SE onset in the mouse hippocampus, activation of brain-resident microglia, and brain recruitment of CCR2+ monocytes. Moreover, we have shown that limiting brain monocyte entry by global Ccr2 KO or CCR2 antagonism rescued several adverse SE-induced effects including blood-brain barrier (BBB) erosion, microgliosis, and neuronal damage (Varvel et al., PNAS 2016; Aleman-Ruiz et al., Scientific Reports 2023). Here we asked if fleeting exposure to a CCR2 antagonist offers protection against cognitive impairments associated with SE.


Methods: Male 8-week-old C57BL/6NCrl mice were administered pilocarpine to induce SE for one hour; SE was interrupted with diazepam. NonSE controls were given saline. Surviving mice were then randomized into vehicle or CCR2 antagonist treatment groups with oral drug treatments 24 and 48 hours after SE onset. Four weeks after SE, the mice were subject to a battery of behavioral tests to assess cognitive performance. Working memory was assessed in the Y-maze, open field (OF) was used to investigate locomotion and anxiety-like behavior, and the novel object recognition test (NORT) was utilized to examine short- and long-term memory, two and 24 hours after the familiarization training phases, respectively.


Results: Compared to nonSE controls, working memory was impaired in SE mice subject to vehicle, and the working memory deficit was alleviated in SE mice given the CCR2 antagonist. In the OF arena, SE mice spent significantly less time in the center anxiogenic zone than their nonSE counterparts indicating that SE enhances anxiety-like behavior. CCR2 antagonism did not reduce the anxiety-like behavior in SE mice. When the NORT was performed 2 hours after the familiarization phase, SE-induced deficits were not observed, indicating that short-term recognition memory was intact after SE. In contrast, recognition memory was impaired in SE mice when the NORT was performed 24 hours after the familiarization phase. This long-term retention memory was preserved in SE mice subject to the CCR2 antagonist. In sum, our findings demonstrate that CCR2 antagonism rescues SE-induced working memory and long-term retention memory deficits.


Conclusions: These findings reinforce the pathological role of brain invading CCR2-expressing monocytes after SE and provide further evidence for the idea that targeting peripheral monocytes with fleeting CCR2 antagonism after SE could represent a novel strategy for alleviating cognitive comorbidities associated with neurologic disease.


Funding:
Supported by NS112350 (NHV) and NS112308 (RD,NHV).