Toll-like Receptor 4 and High-mobility Group Box-1 Are Involved in Ictogenesis and Can Be Targeted to Reduce Seizures

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2010 Mar 30

PMID 20348922

Citations 421

Authors

Mattia Maroso

Silvia Balosso

Teresa Ravizza

Jaron Liu

Eleonora Aronica

Anand M Iyer

Carlo Rossetti

Monica Molteni

Maura Casalgrandi

Angelo A Manfredi

Marco E Bianchi

Annamaria Vezzani

Affiliations

Soon will be listed here.

Abstract

Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1beta (IL-1beta), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.

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