[Frontiers in Bioscience S2, 1081-1091, June 1, 2010]

Targeting HMGB1/TLR4 signaling as a novel approach to treatment of cerebral ischemia

Qing-Wu Yang, Jing Xiang, Yu Zhou, Qi Zhong, Jing-Cheng Li

Department of Neurology, Daping Hospital, The Third Military Medical University, 10 Changjiang Branch Road, Yuzhong District, Chongqing 400042, China

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The role of HMGB1 in the brain
4. TLR4 as a key receptor for HMGB1 in the brain
5. HMGB1/TLR4 signaling pathways
6. Role of HMGB1 in cerebral ischemia
7. Role of TLR4 in cerebral ischemia
8. HMGB1.TLR4-targeted therapies in cerebral ischemia
8.1. HMGB1 as a target of therapy in cerebral ischemia
8.2. TLR4 as a target of therapy in cerebral ischemia
9. Perspective and conclusions
10. Acknowledgments
11.References

1. ABSTRACT

HMGB1 is a ubiquitous, highly conserved DNA-binding protein with well-established functions in the maintenance of nuclear homeostasis. Much of the recent work about its signaling functions in the brain has focused on its proinflammatory properties and relationship to known inflammatory receptors such as toll-like receptor 4 (TLR4). HMGB1 is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain, indicating that HMGB1 acts as a novel mediator in cerebral ischemic injury. Consistently, numerous reports point to TLR4 as a pivotal player in the ischemic brain. The use of HMGB1 and TLR4 ligand as preconditioning stimulus may be benefit of the outcome of cerebral ischemia. Therefore, this review presents the latest findings supporting the involvement of HMGB1 and TLR4 in cerebral ischemia. Targeting HMGB1/TLR4 signaling may provide a novel therapeutic approach for clinical prevention of cerebral ischemic injury.