Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures

M Maroso, S Balosso, T Ravizza, J Liu, E Aronica… - Nature medicine, 2010 - nature.com
M Maroso, S Balosso, T Ravizza, J Liu, E Aronica, AM Iyer, C Rossetti, M Molteni…
Nature medicine, 2010nature.com
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 …
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-1β (IL-1β), 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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