Levetiracetam Suppresses the Infiltration of Neutrophils and Monocytes and Downregulates Many Inflammatory Cytokines during Epileptogenesis in Pilocarpine-Induced Status Epilepticus Mice

Abstract

Acute brain inflammation after status epilepticus (SE) is involved in blood–brain barrier (BBB) dysfunction and brain edema, which cause the development of post-SE symptomatic epilepsy. Using pilocarpine-induced SE mice, we previously reported that treatment with levetiracetam (LEV) after SE suppresses increased expression levels of proinflammatory mediators during epileptogenesis and prevents the development of spontaneous recurrent seizures. However, it remains unclear how LEV suppresses neuroinflammation after SE. In this study, we demonstrated that LEV suppressed the infiltration of CD11b+CD45high cells into the brain after SE. CD11b+CD45high cells appeared in the hippocampus between 1 and 4 days after SE and contained Ly6G+Ly6C+ and Ly6G−Ly6C+ cells. Ly6G+Ly6C+ cells expressed higher levels of proinflammatory cytokines such as IL-1β and TNFα suggesting that these cells were inflammatory neutrophils. Depletion of peripheral Ly6G+Ly6C+ cells prior to SE by anti-Ly6G antibody (NIMP-R14) treatment completely suppressed the infiltration of Ly6G+Ly6C+ cells into the brain. Proteome analysis revealed the downregulation of a variety of inflammatory cytokines, which exhibited increased expression in the post-SE hippocampus. These results suggest that Ly6G+Ly6C+ neutrophils are involved in the induction of acute brain inflammation after SE. The proteome expression profile of the hippocampus treated with LEV after SE was similar to that after NIMP-R14 treatment. Therefore, LEV may prevent acute brain inflammation after SE by suppressing inflammatory neutrophil infiltration.

Impact of levetiracetam on cognitive impairment, neuroinflammation, oxidative stress, and neuronal apoptosis caused by lipopolysaccharides in rats

“…Earlier, it has been shown that LEVE reduces microglial activation and decreases TNF-α and Il-1 levels in the ischemic brain ( Yao et al, 2021 ). Moreover, reduction in hippocampal IL-1β and TNFα levels in status epileptics and IL-1β, TNF- α, IL-4, and IL-6 levels in traumatic brain injury have been also reported after LEVE treatment ( Matsuo et al, 2022 , Bayhan et al, 2020 ). Presently, the levels of pro- and anti-inflammatory mediators were determined to confirm the cytokine expressions after LPS treatment.…”

“…In parallel, our earlier report highlighted that LEVE treatment declined the collection of inflammatory markers like COX-2, NF-κB, prostaglandin E2 (PGE2), and TNF-α in a doxorubicin-induced chemobrain ( Mani et al, 2022a ). According to a recent study, LEVE has an impact on the augmentation of brain inflammation by preventing monocyte and neutrophil infiltrations into the hippocampus and the occurrence of spontaneous recurrent seizures caused by SE ( Matsuo et al, 2022 ).…”

“…Current research reported that elevated expression of pro-inflammatory cytokine levels during epileptogenesis after status epilepticus (SE) was suppressed by LEVE. In continuation, the treatment of LEVE declined mononuclear phagocyte phagocytosis and cytokine expression within two days later SE ( Matsuo et al, 2022 , Itoh et al, 2016 ). Also, LEVE inhibited BV-2 microglial stimulation in vitro , which was evidenced by phagocytic activity, cytokine expressions, and morphological changes ( Itoh et al, 2019 ).…”

Suppressive Effects of Docosahexaenoic Acid Intake on Increased Seizure Susceptibility after Growth Due to Febrile Seizures in Infancy

“…37,38) We reported that Ly6G + Ly6C + neutrophils and microglia were involved in the induction of acute brain inflammation after status epilepticus in pilocarpine-treated mice. 39,40) The present study evaluated CD11b + CD45 low microglial activity by measuring CD68 expression. CD68 expression significantly increased 1 d to 1 week after complex febrile seizures, and this increase recovered to basal levels.…”

Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation

“…Pavone et al found that new AEDs gabapentin, lamotrigine, tiagabine, and LEV did not exert toxic effects on primary rat astrocytes at low and high concentrations, proving that these new AEDs can prevent inflammation, neuronal damage, and death upon pathological stimuli, such as TBI and/or epilepsy ( Pavone and Cardile, 2003 ). Recent studies have suggested that LEV prevents acute neuroinflammation by suppressing inflammatory neutrophil (CD11b+ CD45 + ) infiltration after status epilepticus (SE) ( Matsuo et al, 2022 ). In another study, LEV might inhibit astrocyte reactivity by decreasing the number of A2 astrocyte markers ( Komori et al, 2022 ).…”