Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice

Abstract

Inflammatory processes in brain tissue have been described in human epilepsy of various etiologies and in experimental models of seizures. High mobility group box-1 (HMGB1) is now recognized as representative of damage-associated molecular patterns (DAMPs). In the present study, we focused on whether anti-HMGB1 antibody treatment could relieve status epilepticus- triggered BBB breakdown and inflammation response in addition to the seizure behavior itself. Pilocarpine and methyl-scopolamine were used to establish the acute seizure model. Anti-HMGB1 mAb showed inhibitory effects on leakage of the BBB, and on the HMGB1 translocation induced by pilocarpine. The expression of inflammation-related factors, such as MCP-1, CXCL-1, TLR-4, and IL-6 in hippocampus and cerebral cortex were down-regulated by anti-HMGB1 mAb associated with the number of activated astrocytes, microglial cells as well as the expression of IL-1β. Both hematoxylin & eosin and TUNEL staining showed that the apoptotic cells could be reduced after anti-HMGB1 mAb treatment. The onset and latency of Racine stage five were significantly prolonged in the anti-HMGB1 mAb group. These results suggested that anti-HMGB1 mAb prevented the BBB permeability, reduced HMGB1 translocation while inhibiting the expression of inflammation-related factors, protected against neural cell apoptosis and prolonged Racine stage 5 seizure onset and latency.

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

“…After pro‐convulsant (pilocarpine) administration in mice, a release of HMGB1 into the CNS and peripheral bloodstream was found to contribute to the induction of BBB disruption and activation of inflammatory mediators leading to epilepsy (Fu et al . ).…”

“…Administration of recombinant human HMGB1 promoted Evans Blue leakage further in a dose‐dependent fashion, which suggests that HMGB1 promotes the BBB breakdown in an epileptic state (Fu et al . ).…”

“…These findings support the notion that there is HMGB1 translocation and release in the CA1 and cerebral cortex area during an acute epileptic state (Fu et al . ). In a KA‐induced C57BL/6 mice, expression level and distribution of HMGB1 after KA induction suggest that HMGB1 immunoreactivity was mostly located inside the nuclei of the pyramidal neurons in the normal group.…”

“…Arrays of studies have repeatedly reported the release of HMGB1 from nuclei in a range of neurological disorders including epilepsy (Fu et al . ; Zhao et al . ; Angelopoulou et al .…”

“…HMGB1 has emerged as a novel target against epileptogenesis, but much remained to be explored before translating it to patients (Fu et al . ). Herein, we highlight and update on key concepts ranging from HMGB1 biology, its role in epileptogenesis, available HMGB1 inhibitors and experimental evidence of HMGB1 as an anti‐epileptic therapy.…”