Molecular Neurobiology

, Volume 53, Issue 4, pp 2339–2353 | Cite as

HO-1 Signaling Activation by Pterostilbene Treatment Attenuates Mitochondrial Oxidative Damage Induced by Cerebral Ischemia Reperfusion Injury

  • Yang Yang
  • Jiayi Wang
  • Yue Li
  • Chongxi Fan
  • Shuai Jiang
  • Lei Zhao
  • Shouyin Di
  • Zhenlong Xin
  • Bodong Wang
  • Guiling Wu
  • Xia Li
  • Zhiqing Li
  • Xu Gao
  • Yushu DongEmail author
  • Yan QuEmail author


Ischemia reperfusion (IR) injury (IRI) is harmful to the cerebral system and causes mitochondrial oxidative stress. The antioxidant response element (ARE)-mediated antioxidant pathway plays an important role in maintaining the redox status of the brain. Heme oxygenase-1 (HO-1), combined with potent AREs in the promoter of HO-1, is a highly effective therapeutic target for protection against cerebral IRI. Pterostilbene (PTE), a natural dimethylated analog of resveratrol from blueberries, is a strong natural antioxidant. PTE has been shown to be beneficial for some nervous system diseases and may regulate HO-1 signaling. This study was designed to investigate the protective effects of PTE on cerebral IRI and to elucidate potential mechanisms underlying those effects. Mouse brains and cultured HT22 neuron cells were subjected to IRI. Prior to this procedure, the brains or cells were exposed to PTE in the absence or presence of the HO-1 inhibitor ZnPP or HO-1 small interfering RNA (siRNA). PTE conferred a cerebral protective effect, as shown by increased neurological scores, viable neurons and decreased brain edema as well as a decreased ion content and apoptotic ratio in vivo. PTE also increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules: NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTs), which are induced by PTE. PTE also promoted a well-preserved mitochondrial membrane potential (MMP), mitochondria complex I activity, and mitochondria complex IV activity, increased the mitochondrial cytochrome c level, and decreased the cytosolic cytochrome c level. However, this PTE-elevated mitochondrial function was reversed by ZnPP or HO-1 siRNA treatment. In summary, our results demonstrate that PTE treatment attenuates cerebral IRI by reducing IR-induced mitochondrial oxidative damage through the activation of HO-1 signaling.


Ischemia reperfusion Pterostilbene HO-1 signaling Mitochondrial oxidative damage Cerebral protection 



This study was supported by grants from the National Natural Science Foundation of China (81222015) and the New Century Talent Supporting Project by Chinese education ministry (NCET-12-1004).

Conflict of Interest

The grants from the authors have no disclosures to declare.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yang Yang
    • 1
    • 4
  • Jiayi Wang
    • 1
  • Yue Li
    • 3
  • Chongxi Fan
    • 5
  • Shuai Jiang
    • 1
  • Lei Zhao
    • 1
  • Shouyin Di
    • 5
  • Zhenlong Xin
    • 1
  • Bodong Wang
    • 1
  • Guiling Wu
    • 1
  • Xia Li
    • 1
  • Zhiqing Li
    • 2
  • Xu Gao
    • 2
  • Yushu Dong
    • 2
  • Yan Qu
    • 1
  1. 1.Department of Neurosurgery, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina
  2. 2.Department of NeurosurgeryGeneral Hospital of Shenyang Military Area CommandShenyangChina
  3. 3.Department of Air LogisticsThe 463rd Hospital of PLAShenyangChina
  4. 4.Department of Biomedical EngineeringThe Fourth Military Medical UniversityXi’anChina
  5. 5.Department of Thoracic Surgery, Tangdu HospitalThe Fourth Military Medical UniversityXi’anChina

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