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Neuroprotective Effect of Oxysophocarpine by Modulation of MAPK Pathway in Rat Hippocampal Neurons Subject to Oxygen–Glucose Deprivation and Reperfusion

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Abstract

Oxysophocarpine (OSC), an alkaloid isolated from Sophora flavescens Ait, has been traditionally used as a medicinal agent based on the observed pharmacological effects. In this study, the direct effect of OSC against neuronal injuries induced by oxygen and glucose deprivation (OGD) in neonatal rat primary-cultured hippocampal neurons and its mechanisms were investigated. Cultured hippocampal neurons, which were exposed to OGD for 2 h followed by a 24 h reoxygenation, were used as an in vitro model of ischemia and reperfusion. 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) assay were used to confirm neural damage and to further evaluate the protective effects of OSC. The concentration of intracellular-free calcium [Ca2+]i and mitochondrial membrane potential (MMP) were measured to determine the intracellular mechanisms and to further estimate the degree of neuronal damage. Changes in expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, p-ERK1/2, p-JNK1/2, and p-p38 MAPK were also observed in the in vitro model. It was shown that OSC (0.8, 2, or 5 µmol/L) significantly attenuated the increased absorbance of MTT, and the release of LDH manifests the neuronal damage by the OGD/R. Meanwhile, the pretreatment of the neurons during the reoxygenation period with OSC significantly increased MMP; it also inhibited [Ca2+]i the elevation in a dose-dependent manner. Furthermore, the pretreatment with OSC (0.8, 2, or 5 µmol/L) significantly down-regulated expressions of IL-1β, TNF-α, p-ERK1/2, p-JNK1/2, and p-p38 MAPK in neonatal rat primary-cultured hippocampal neurons induced by OGD/R injury. In conclusion, OSC displays a protective effect on OGD-injured hippocampal neurons by attenuating expression of inflammatory factors via down-regulated the MAPK signaling pathway.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant no. 81660674) and the Ningxia Natural Science Foundation (Grant no. NZ15149), the Ningxia Hui Autonomous Region science and technology support program (2015BAK45B01), and the key research project of the health department of the Autonomous Region (2012059) and Special talents scientific research project (XT2012015). We are indebted to the staff at the animal center and the Science and Technology Center who provided assistance in the study.

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  1. Peng Zhao and Ren-Yuan Chang have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China

    Peng Zhao, Ren-Yuan Chang, Ning Liu, Jing Wang, Ru Zhou, Xue Qi, Yue Liu & Jian-Qiang Yu

  2. Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China

    Yang Niu

  3. Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, China

    Lin Ma & Tao Sun

  4. College of Nursing, Ningxia Medical University, Yinchuan, China

    Yu-Xiang Li

  5. General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, China

    Yan-Ping He

  6. Ningxia Hui Medicine Modern Engineering Research Center, Ningxia Medical University, Yinchuan, China

    Jian-Qiang Yu

  7. Pharmacy Department of Yulin First Hospital, Shaanxi, China

    Ren-Yuan Chang

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  1. Peng Zhao
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Correspondence to Yan-Ping He or Jian-Qiang Yu.

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Zhao, P., Chang, RY., Liu, N. et al. Neuroprotective Effect of Oxysophocarpine by Modulation of MAPK Pathway in Rat Hippocampal Neurons Subject to Oxygen–Glucose Deprivation and Reperfusion. Cell Mol Neurobiol 38, 529–540 (2018). https://doi.org/10.1007/s10571-017-0501-5

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