Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway.

Yi Ding,Yanyan Jia,Tiejun Zhang,Mingming Wang,Aidong Wen,Yanrong Zhu,Jongsun Park,Min Wang,Minchun Chen,Chao Guo,Yuwen Li

doi:10.1038/srep07002

Abstract

Stroke is a complex disease involved oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. Acetyl-11-Keto-β-Boswellic Acid (AKBA) is an active triterpenoid compound from the extract of Boswellia serrate. The present study was to determine whether AKBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. The stroke model was produced in Sprague–Dawley rats via middle cerebral artery occlusion. To model ischemia-like conditions in vitro, primary cultured cortical neurons were exposed to transient oxygen and glucose deprivation (OGD). Treatment of AKBA significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores by elevating the Nrf2 and HO-1 expression in brain tissues in middle cerebral artery occlusion (MCAO) rats at 48 hours post reperfusion. In primary cultured neurons, AKBA increased the Nrf2 and HO-1 expression, which provided protection against OGD-induced oxidative insult. Additionally, AKBA treatment increased Nrf2 binding activity to antioxidant-response elements (ARE). The protective effect of AKBA was attenuated by knockdown of Nrf2 or HO-1. In conclusion, these findings provide evidence that AKBA protects neurons against ischemic injury, and this neuroprotective effect involves the Nrf2/HO-1 pathway.

Highlights

Stroke is a complex disease involved oxidative stress-related pathways in its pathogenesis
We hypothesized that Acetyl-11-Keto-b-Boswellic Acid (AKBA) would provide neuroprotection against I/R injury induced by transient middle cerebral artery occlusion (MCAO) in rats and oxygen and glucose deprivation (OGD) in primary cultured neurons, and that the protection would occur through activation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/HO1 pathway
The ischemic cascade begins with a drastic disruption of cerebral blood flow that deprives brain cells of oxygen and glucose supply, leading to a decrease in energy production associated with building up toxic substances such as glutamate, inflammatory mediators, and free radicals that could result in neurodegeneration

Summary

Introduction

Stroke is a complex disease involved oxidative stress-related pathways in its pathogenesis. It was reported that ursolic acid, a naturally occurring pentacyclic triterpenoid, promotes the neuroprotection after cerebral ischemia in mice by activating Nrf[2] pathway[8]. HO-1 has been reported to have the most AREs on its promoter, making it a highly effective therapeutic target for protection against neurodewww.nature.com/scientificreports generative diseases It gives protection in part by degrading its prooxidant substrate, heme, and generating the antioxidants biliverdin and bilirubin[12]. Studies have provided evidence for the therapeutic potential of targeting the Nrf2/HO-1 pathway in brain injury after ischemic stroke[13,14]. We hypothesized that AKBA would provide neuroprotection against I/R injury induced by transient middle cerebral artery occlusion (MCAO) in rats and oxygen and glucose deprivation (OGD) in primary cultured neurons, and that the protection would occur through activation of the Nrf2/HO1 pathway

Methods

Results

Conclusion