期刊
NATURE MEDICINE
卷 16, 期 4, 页码 413-U91出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2127
关键词
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资金
- CARIPLO Foundation
- Parents Against Childhood Epilepsy
- Associazione Italiana Contro l'Epilessia
- EU [LSH-CT-2006-037315, 202167]
- National Epilepsy Fund [NEF 09-05]
- Regione Lombardia
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-1 beta (IL-1 beta), 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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