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Selective mGluR1 Negative Allosteric Modulator Reduces Blood–Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage

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Abstract

The blood–brain barrier (BBB) disruption leads to the vasogenic brain edema and contributes to the early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the BBB damage following SAH are poorly understood. Here we reported that the neurotransmitter glutamate of cerebrospinal fluid (CSF) was dramatically increased in SAH patients with symptoms of cerebral edema. Using the rat SAH model, we found that SAH caused the increase of CSF glutamate level and BBB permeability in EBI, intracerebroventricular injection of exogenous glutamate deteriorated BBB damage and cerebral edema, while intraperitoneally injection of metabotropic glutamate receptor 1(mGluR1) negative allosteric modulator JNJ16259685 significantly attenuated SAH-induced BBB damage and cerebral edema. In an in vitro BBB model, we showed that glutamate increased monolayer permeability of human brain microvascular endothelial cells (HBMEC), whereas JNJ16259685 preserved glutamate-damaged BBB integrity in HBMEC. Mechanically, glutamate downregulated the level and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), decreased the tight junction protein occludin, and increased AQP4 expression at 72 h after SAH. However, JNJ16259685 significantly increased VASP, p-VASP, and occludin, and reduced AQP level at 72 h after SAH. Altogether, our results suggest an important role of glutamate in disruption of BBB function and inhibition of mGluR1 with JNJ16259685 reduced BBB damage and cerebral edema after SAH.

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Funding

This work was supported by funds from the National Natural Science Foundation of China (Grant No. 81671141 and 81870938), the Taishan Scholars Project (to Bao-liang Sun), the Shanghai Science and Technology Commission (19431903200 to Ming Jiang), and the Youth Innovation Team of Shandong Universities (2019KJK001 to Zong-yong Zhang).

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Author notes

  1. Cheng Zhang, Ming Jiang, Wei-qi Wang and Shi-jun Zhao contributed equally to this work.

Authors and Affiliations

  1. Key Lab of Cerebral Microcirculation of Shandong, First Medical University & Shandong Academy of Medical Sciences, Tai’an, 271016, Shandong, People’s Republic of China

    Cheng Zhang, Wei-qi Wang, Qiong-jie Mi, Ming-feng Yang, Bao-liang Sun & Zong-yong Zhang

  2. Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, People’s Republic of China

    Ming Jiang & Yan-xin Yin

  3. Medical College of Qingdao University, Qingdao, 266021, Shandong, People’s Republic of China

    Wei-qi Wang

  4. Department of Neurology, Baotou Central Hospital, Baotou, 014040, People’s Republic of China

    Shi-jun Zhao

  5. Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, People’s Republic of China

    Yu-qiang Song

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  1. Cheng Zhang
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Contributions

BS and ZZ designed the experiments. CZ, JM, WW, SZ, YY, QM, YS, and MY performed the experiments. ZZ and BS analyzed the results. ZZ wrote the manuscript with contribution from BS. All authors read and approved the final manuscript.

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Correspondence to Bao-liang Sun or Zong-yong Zhang.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Zhang, C., Jiang, M., Wang, Wq. et al. Selective mGluR1 Negative Allosteric Modulator Reduces Blood–Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage. Transl. Stroke Res. 11, 799–811 (2020). https://doi.org/10.1007/s12975-019-00758-z

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