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Erythropoietin Delivered via Intra-Arterial Infusion Reduces Endoplasmic Reticulum Stress in Brain Microvessels of Rats Following Cerebral Ischemia and Reperfusion

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Abstract

Local infusion of low dose erythropoietin (EPO) alleviates cerebral ischemia and reperfusion (I/R) injury in rats; however, the underlying molecular mechanisms are still unclear. The present study investigated the effect of low dose EPO treatment on I/R-induced endoplasmic reticulum (ER) stress in brain tissue and isolated microvessels in rodents. Sprague-Dawley rats were subjected to 2 h ischemia/24 h reperfusion by middle cerebral artery (MCA) occlusion, then administered fluorescein isothiocyanate-labeled EPO via MCA infusion (MCAI) or subcutaneous injection (SI) to compare the efficiency of two modes of delivery. Neurobehavioral deficits and infarct volume, and the expression of ER stress-associated proteins and apoptosis in brain tissue or isolated microvessels, as well as the transcriptional activity of 16 factors involved in ER stress and the unfolded protein response in brain tissue was asscessed. A higher EPO level in cerebrospinal fluid and brain tissue was observed in rats treated with EPO by MCAI (800 IU/kg) than by SI (5000 IU/kg). Moreover, neurobehavioral deficits and infarct volume were reduced in rats treated with EPO by MCAI and salubrinal. EPO suppressed the expression of ER stress signals glucose-regulated protein 78, activating transcription factor (ATF) 6α, and CCAAT enhancer-binding protein homologous protein (CHOP), as well as that of the pro-apoptotic protein caspase-3 in brain microvessels, and decreased the number of CHOP-positive, apoptotic neurons. EPO treatment also reduced the transcriptional activities of CHOP, forkhead box protein O1, and ATF4. These results provide evidence that low dose EPO treatment via MCAI provides neuroprotection following acute ischemic stroke by inhibiting the ER stress response.

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Acknowledgments

The authors thank Jinhuan Gao (Xuanwu Hospital of Capital Medical University) for her excellent technical assistance. This project was supported by the Natural Science Foundation of China (nos. 81071058, 30670725, 81271461, and 81201028).

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing, 100053, China

    Haiping Zhao, Rongliang Wang, Xiaoning Wu, Jia Liang, Zhifeng Qi, Xiangrong Liu, Lianqiu Min, Xunming Ji & Yumin Luo

  2. Key Laboratory for Neurodegenerative Diseases, Ministry of Education, Beijing, China

    Haiping Zhao, Rongliang Wang, Xiaoning Wu, Jia Liang, Zhifeng Qi, Xiangrong Liu, Lianqiu Min, Xunming Ji & Yumin Luo

  3. Department of Neurology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, 121001, Liaoning Province, China

    Haiping Zhao, Rongliang Wang, Xiaoning Wu, Jia Liang, Zhifeng Qi, Xiangrong Liu, Lianqiu Min, Xunming Ji & Yumin Luo

  4. Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China

    Haiping Zhao, Rongliang Wang, Xiaoning Wu, Jia Liang, Zhifeng Qi, Xiangrong Liu, Lianqiu Min, Xunming Ji & Yumin Luo

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  1. Haiping Zhao
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  2. Rongliang Wang
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  3. Xiaoning Wu
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  4. Jia Liang
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  5. Zhifeng Qi
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  6. Xiangrong Liu
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  7. Lianqiu Min
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  8. Xunming Ji
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  9. Yumin Luo
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Correspondence to Yumin Luo.

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Zhao, H., Wang, R., Wu, X. et al. Erythropoietin Delivered via Intra-Arterial Infusion Reduces Endoplasmic Reticulum Stress in Brain Microvessels of Rats Following Cerebral Ischemia and Reperfusion. J Neuroimmune Pharmacol 10, 153–161 (2015). https://doi.org/10.1007/s11481-014-9571-z

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  • DOI: https://doi.org/10.1007/s11481-014-9571-z

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