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Involvement of Endothelin-1, H2S and Nrf2 in Beneficial Effects of Remote Ischemic Preconditioning in Global Cerebral Ischemia-Induced Vascular Dementia in Mice

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Abstract

The present study explored the role of endothelin-1, H2S, and Nrf2 in remote preconditioning (RIPC)-induced beneficial effects in ischemia–reperfusion (I/R)-induced vascular dementia. Mice were subjected to 20 min of global ischemia by occluding both carotid arteries to develop vascular dementia, which was assessed using Morris water maze test on 7th day. RIPC was given by subjecting hind limb to four cycles of ischemia (5 min) and reperfusion (5 min) and it significantly restored I/R-induced locomotor impairment, neurological severity score, cerebral infarction, apoptosis markers along with deficits in learning and memory. Biochemically, there was increase in the plasma levels of endothelin-1 along with increase in the brain levels of H2S and its biosynthetic enzymes viz., cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CLS). There was also an increase in the expression of Nrf2 and glutathione reductase in the brain in response to RIPC. Pretreatment with bosentan (dual blocker of ETA and ETB receptors), amino-oxyacetic acid (CBS synthase inhibitor), and DL-propargylglycine (CLS inhibitor) significantly attenuated RIPC-mediated beneficial effects and biochemical alterations. The effects of bosentan on behavioral and biochemical parameters were more significant than individual treatments with CBS or CLS inhibitors. Moreover, CBS and CLS inhibitors did not alter the endothelin-1 levels possibly suggesting that endothelin-1 may act as upstream mediator of H2S. It is concluded that RIPC may stimulate the release endothelin-1, which may activate CBS and CLS to increase the levels of H2S and latter may increase the expression of Nrf2 to decrease oxidative stress and prevent vascular dementia.

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Funding

The project was supported by Jilin Provincial Department of Finance funds in China (No. Sczsy201512), Jilin Provincial Department of Health funds (No. 20152085), The National Natural Science Fund Projects (No. 81671159), Jilin Province Department of International Cooperation Projects (No. 20170414014GH), Jilin University Outstanding Young Teacher Training Program (No. 450060472325).

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Authors and Affiliations

  1. Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, 130033, Jilin, China

    Jin-Ting He & Haiqi Li

  2. Department of Endocrinology, The People’s Hospital of Jilin Province, Changchun, 130031, China

    Le Yang

  3. Department of Radiology, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun, 130033, Jilin, China

    Kai-Liang Cheng

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  1. Jin-Ting He
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  2. Haiqi Li
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JTH did the experiments; HL helped JTH in experimental work and participated in writing; LY helped in writing the manuscript; KLC conceived the idea and edited the manuscript.

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Correspondence to Le Yang or Kai-Liang Cheng.

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He, JT., Li, H., Yang, L. et al. Involvement of Endothelin-1, H2S and Nrf2 in Beneficial Effects of Remote Ischemic Preconditioning in Global Cerebral Ischemia-Induced Vascular Dementia in Mice. Cell Mol Neurobiol 39, 671–686 (2019). https://doi.org/10.1007/s10571-019-00670-y

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