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Small Interfering RNA Targeting Dickkopf-1 Contributes to Neuroprotection After Intracerebral Hemorrhage in Rats

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Abstract

Excessive Dickkopf-1 (Dkk-1) plays a vital role in secondary brain injury following ischemic stroke and psychotic disease. However, it is unclear whether an increased expression of Dkk-1 occurred after intracerebral hemorrhage (ICH). The present study examined the potential role of Dkk-1 after ICH. ICH was induced by a single injection of autologous blood into the basal ganglia of rats. Dkk-1 protein levels in brain tissue and serum were detected by enzyme-linked immunosorbent assay after ICH. Rats were treated with small interfering RNA targeting Dkk-1 (siDkk-1) or vehicle following ICH. Behavioral deficits and brain water content were examined. Blood–brain barrier (BBB) integrity was detected by Evans blue extravasation and observed by transmission electron microscopy. Wnt-1 was evaluated by real-time RT-PCR. The tight junction protein zonula occludens-1 (ZO-1) was investigated by immunohistochemistry and Western blot assays. Serum level of Dkk-1 did not differ between the ICH and sham groups. However, the level of Dkk-1 in brain tissue was significantly increased at 24 and 72 h after ICH. BBB disruption and brain edema, as well as neurological deficits, were remarkably ameliorated by administration of siDkk-1. Moreover, siDkk-1 treatment significantly increased the transcription of Wnt-1 mRNA and upregulated the expression of ZO-1. These results provide the first evidence that siDkk-1 treatment is neuroprotective against secondary injury including brain edema and BBB permeability following ICH; the mechanism of neuroprotection may be associated with improvement of BBB integrity.

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Abbreviations

ICH:

Intracerebral hemorrhage

Dkk-1:

Dickkopf-1

BBB:

Blood–brain barrier

ZO-1:

Zonula occludens-1

ELISA:

Enzyme-linked immunosorbent assay

TJ:

Tight junction

siDkk-1:

Small interfering RNA targeting Dkk-1

TEM:

Transmission electron microscopy

RT-PCR:

Real-time reverse transcriptase-polymerase chain reaction

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (U1204807), the Science and Technology Department of Henan Province (201304013, 132300410112), and the Educational Department of Henan Province (17A310008).

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Authors and Affiliations

  1. Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China

    Zhihua Li, Xiuhua Ren, Xuemei Chen, Jing Cao & Weidong Zang

  2. Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1 the Jianshe East Road, Zhengzhou, Henan Province, 450052, People’s Republic of China

    Zhihua Li, Xi Chen, Xiaoyang Zhang, Xianzhi Liu & Fuyou Guo

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  1. Zhihua Li
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  2. Xi Chen
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Correspondence to Fuyou Guo.

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Li, Z., Chen, X., Zhang, X. et al. Small Interfering RNA Targeting Dickkopf-1 Contributes to Neuroprotection After Intracerebral Hemorrhage in Rats. J Mol Neurosci 61, 279–288 (2017). https://doi.org/10.1007/s12031-017-0883-3

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