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Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

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Abstract

Multiple players are involved in motor and sensory dysfunctions after spinal cord injury (SCI). Therefore, therapeutic approaches targeting these various players in the damage cascade hold considerable promise for the treatment of traumatic spinal cord injury. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). sEH inhibition has been shown to provide neuroprotective effects upon multiple elements of neurovascular unit under cerebral ischemia. However, its role in the pathological process after SCI remains unclear. In this study, we tested the hypothesis that sEH inhibition may have therapeutic effects in preventing secondary damage in rats after traumatic SCI. sEH was widely expressed in spinal cord tissue, mainly confined to astrocytes, and neurons. Administration of sEH inhibitor AUDA significantly suppressed local inflammatory responses as indicated by the reduced microglia activation and IL-1 β expression, as well as the decreased infiltration of neutrophils and T lymphocytes. Meanwhile, reactive astrogliosis was remarkably attenuated. Furthermore, treatment of AUDA improved angiogenesis, inhibited neuron cells apoptosis, alleviated demyelination and formation of cavity and improved motor recovery. Together, these results provide the first in vivo evidence that sEH inhibition could exert multiple targets protective effects after SCI in rats. sEH may thereby serve as a promising multi-mechanism therapeutic target for the treatment of SCI.

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Acknowledgments

The investigation was supported by the National Natural Science Foundation of China (81371312, 61327902, 30971007), National Basic Research Development Program (973 Program) of China (2011CB504403) and Natural Science Foundation of Hubei Province (2014CFB445). The authors declare no competing financial interests.

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    Authors and Affiliations

    1. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

      Xiaojing Chen, Xiaojiang Huang, Chuan Qin, Yongkang Fang, Yang Liu, Dengji Pan, Wei Wang & Minjie Xie

    2. Department of Neurology, Xinhua Hospital of Hubei Province, Wuhan, 430015, People’s Republic of China

      Xiaoqi Chen

    3. Department of neurology, Xiangyang hospital affiliated to Hubei University of Medicine, Xiangyang, People’s Republic of China

      Guibing Zhang

    4. Department of Neurology, Nanyang City Center Hospital, Nanyang, 473000, People’s Republic of China

      Xiaojing Chen

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    Correspondence to Minjie Xie.

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    Xiaojing Chen and Xiaoqi Chen contributed equally to this work.

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    Chen, X., Chen, X., Huang, X. et al. Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury. Mol Neurobiol 53, 1565–1578 (2016). https://doi.org/10.1007/s12035-015-9118-1

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