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Posttreatment with 11-Keto-β-Boswellic Acid Ameliorates Cerebral Ischemia–Reperfusion Injury: Nrf2/HO-1 Pathway as a Potential Mechanism

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Abstract

Oxidative stress is well known to play a pivotal role in cerebral ischemia–reperfusion injury. 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. 11-Keto-β-boswellic acid (KBA) is a triterpenoid compound from extracts of Boswellia serrata. The aim of the present study was to determine whether KBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was operated on male Sprague–Dawley rats. KBA (25 mg/kg) applied 1 h after reperfusion significantly reduced infarct volumes and apoptotic cells as well as increased neurologic scores at 48 h after reperfusion. Meanwhile, posttreatment with KBA significantly decreased malondialdehyde (MDA) levels, restored the superoxide dismutase (SOD) activity, and increased the protein Nrf2 and HO-1 expression in brain tissues. In primary cultured astrocytes, KBA increased the Nrf2 and HO-1 expression, which provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. But knockdown of Nrf2 or HO-1 attenuated the protective effect of KBA. In conclusion, these findings provide evidence that the neuroprotection of KBA against oxidative stress-induced ischemic injury involves the Nrf2/HO-1 pathway.

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Abbreviations

KBA:

11-Keto-β-boswellic acid

ARE:

Antioxidant response elements

CBF:

Cerebral blood flow

EMSA:

Electrophoresis mobility shift assay

GPx:

Glutathione peroxidase

I/R:

Ischemia–reperfusion

HE:

Hematoxylin and eosin

HO-1:

Heme oxygenase-1

Keap1:

Kelch-like ECH-associated protein 1

MCAO:

Middle cerebral artery occlusion

MDA:

Malondialdehyde

MTT:

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

Nrf2:

Nuclear factor erythroid-2-related factor 2

OGD:

Oxygen and glucose deprivation

PBS:

Phosphate-buffered saline

ROS:

Reactive oxygen species

SD:

Standard deviation

siRNA:

Small interfering RNA

SOD:

Superoxide dismutase

TTC:

2,3,5-Triphenyltetrazolium chloride

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Acknowledgments

This work received the support of the grant from the Key Technologies for New Drug Innovation and Development of China (No. 2011ZXJ09202-13; No. 2012BAK25B00) and National Natural Science Foundation of China (No.81373947; No.81201985).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, China

    Yi Ding, MinChun Chen, MingMing Wang, YuWen Li & AiDong Wen

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Ding, Y., Chen, M., Wang, M. et al. Posttreatment with 11-Keto-β-Boswellic Acid Ameliorates Cerebral Ischemia–Reperfusion Injury: Nrf2/HO-1 Pathway as a Potential Mechanism. Mol Neurobiol 52, 1430–1439 (2015). https://doi.org/10.1007/s12035-014-8929-9

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