Daphnetin Protects against Cerebral Ischemia/Reperfusion Injury in Mice via Inhibition of TLR4/NF-κB Signaling Pathway.

Jia Liu,Xiaoxing Xiong,Lei Wang,Xiqun Zhu,Zhihong Jian,Tong Jin,Qianxue Chen,Lingmin Shao

doi:10.1155/2016/2816056

Jia Liu, Xiaoxing Xiong + Show 6 more

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https://doi.org/10.1155/2016/2816056

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Abstract

Growing evidences indicate that immune-mediated mechanisms contribute to the development of cerebral ischemia/reperfusion (I/R) injury. Daphnetin (DAP) is a coumarin derivative extracted from Daphne odora var., which displays anti-inflammatory properties. However, the effect of DAP on cerebral I/R injury is not yet clear. Recent studies have demonstrated that TLR4/NF-κB signaling pathway takes part in the damaging inflammatory process of cerebral I/R injury. The present study aimed to investigate the effect of DAP on cerebral I/R injury in vivo and its possible mechanisms. DAP was administered before middle cerebral artery occlusion and reperfusion in mice. The neurological scores, cerebral infarct sizes, the levels of inflammatory cytokines, apoptotic neural cells, and the levels of TLR4, NF-κB p65, and IκBα were estimated. The results showed that an obvious improvement of neurological scores and infarct sizes was observed in DAP-treated mice after MCAO/R. DAP treatment decreased the overexpression of TNF-α, IL-1β, and IL-6 and attenuated neural cells apoptosis. Moreover, DAP treatment decreased the TLR4 expression, IκB-α degradation, and nuclear translocation of NF-κB. Taken together, our results suggested that DAP exerted neuroprotective and anti-inflammatory effects on cerebral I/R injury. The potential mechanism was involved in the inhibition of TLR4/NF-κB mediated inflammatory signaling pathway.

Highlights

Ischemic stroke is a leading cause of mortality and disability in adults worldwide [1]
To determine the neuroprotective effects of DAP against cerebral I/R injury, we assessed the neurological scores and cerebral infarct sizes 24 hours after Middle Cerebral Artery Occlusion and Reperfusion (MCAO/R) (Figure 2). 5 mg/kg of DAP did not affect the neurologic scores or infarct sizes compared with the vehicle (P > 0.05)
DAP treatment remarkably decreased the degradation of IκBα (P < 0.05). These results suggested that the Toll-like receptor 4 (TLR4)/NF-κB signaling pathway was involved with the protective effects of DAP on cerebral I/R injury

Summary

Introduction

Ischemic stroke is a leading cause of mortality and disability in adults worldwide [1]. Administration of intravenous thrombolysis with tissue plasminogen activator (tPA) is currently approved for the treatment of ischemic stroke. A secondary impairment known as cerebral ischemia/reperfusion (I/R) injury comes up with the t-PA treatment [2]. It results from a complex pattern of pathophysiological events. The critical role of immune-mediated mechanisms in cerebral I/R injury has been increasingly recognized in the last decades [3] and the important contribution of Toll-like receptors (TLRs) in the induction of inflammatory responses has been demonstrated [4]. Toll-like receptor 4 (TLR4) was found to be highly induced after cerebral I/R [5]. TLR4/NF-κB signaling pathway may be a therapeutic target for cerebral I/R injury

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