Abstract
Background: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. Methods: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. Results: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. Conclusion: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.
Highlights
Stroke is a common clinical disease with detrimental personal, social, and economic impacts [1]
We investigated the therapeutic effects of Emodin on ischemic brain injury and propose additional mechanisms explaining these neuroprotective effects involving glutamate and the glutamate transporter glutamate transporter-1 (GLT-1)
There was no difference between normoxia and oxygen-glucose deprivation (OGD)-hypoxia; cell viability decreased over time
Summary
Stroke is a common clinical disease with detrimental personal, social, and economic impacts [1]. Evidence indicates that several signaling molecules and transcription factors are involved in ischemia-induced cell apoptosis [5,6] These mediators include calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK), nuclear factor-κB (NF-κB), and the signal transducer and activator of transcription 1(STAT1) [7]. The neuroprotective effect of Emodin was first published in 2005 when its ability to interfere with the release of glutamate was identified as a method of neuroprotection [16] Since both in vitro and in vivo experiments have shown the neuroprotective effects of Emodin against cerebral ischemia-reperfusion injury and glutamate-induced neural injury [17]. We investigated the therapeutic effects of Emodin on ischemic brain injury and propose additional mechanisms explaining these neuroprotective effects involving glutamate and the glutamate transporter GLT-1
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