Neuroprotection of Tanshinone IIA against Cerebral Ischemia/Reperfusion Injury through Inhibition of Macrophage Migration Inhibitory Factor in Rats

Yanlin Chen,Lan Li,Jing Zhao,Xuemei Wu,Yong Zhao,Shanshan Yu,Xuemei Lin,Jingxian Wu,Wing-Ho Yung

doi:10.1371/journal.pone.0040165

Yanlin Chen, Lan Li + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0040165

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Journal: PloS one	Publication Date: Jun 29, 2012
Citations: 103	License type: CC BY 4.0

Affiliation: Chongqing Medical University

Abstract

BackgroundIschemia/reperfusion (I/R) injury is associated with systemic inflammatory response. Macrophage migration inhibitory factor (MIF) has been implicated in many inflammatory processes. Tanshinone IIA (TSA) is one of the active ingredients in danshen, which derived from the dried root or rhizome of Salviae miltiorrhizae Bge. Recent studies have demonstrated that TSA has protective effects against focal cerebral I/R injury. However, little is known about the underlying mechanisms. Here we put forward the hypothesis that TSA acts through inhibition of MIF expression during focal cerebral I/R injury in rats.Methodology/Principal FindingsRats were subjected to middle cerebral artery occlusion (MCAO) for 2 hours. This was followed by reperfusion. We measured neurological deficits, brain water content, and infarct volume, and found that neurological dysfunction, brain edema, and brain infarction were significantly attenuated by TSA 6 hours after reperfusion. We also measured myeloperoxidase (MPO) activity at 6 and 24 hours, and found that neutrophil infiltration was significantly higher in the vehicle+I/R group than in the TSA+I/R group. ELISA demonstrated that TSA could inhibit MIF expression and the release of TNF-α and IL-6 induced by I/R injury. Western blot analysis and immunofluorescence staining showed that MIF expression was significantly lower in the TSA+I/R group than in the vehicle+I/R group. MIF was found almost all located in neurons and hardly any located in astrocytes in the cerebral cortex. Western blot analysis and EMSA demonstrated that NF-κB expression and activity were significantly increased in the vehicle+I/R group. However, these changes were attenuated by TSA.Conclusion/SignificanceOur results suggest that TSA helps alleviate the proinflammatory responses associated with I/R-induced injury and that this neuroprotective effect may occur through down-regulation of MIF expression in neurons.

Highlights

Stroke is the second most common cause of death and a major cause of disability worldwide [1,2]
middle cerebral artery occlusion (MCAO) is a classical model of cerebral ischemia [17,18]
We have shown that Tanshinone IIA (TSA) can reduce MPO activity after focal cerebral I/R injury

Summary

Introduction

Stroke is the second most common cause of death and a major cause of disability worldwide [1,2]. The selective inhibition of inflammatory cytokine activity remains an important goal in the effective treatment of brain ischemia and reperfusion (I/R) injury. There is ample evidence indicating that MIF expression is increased at the transcriptional level in human stroke patients and in animal models of focal ischemia [9]. This suggests that inhibition of MIF may serve as a viable strategy for the treatment of ischemic stroke. Tanshinone IIA (TSA) is one of the active ingredients in danshen, which derived from the dried root or rhizome of Salviae miltiorrhizae Bge. Recent studies have demonstrated that TSA has protective effects against focal cerebral I/R injury. We put forward the hypothesis that TSA acts through inhibition of MIF expression during focal cerebral I/ R injury in rats

Methods

Results

Conclusion