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A Cannabinoid Receptor 2 Agonist Prevents Thrombin-Induced Blood–Brain Barrier Damage via the Inhibition of Microglial Activation and Matrix Metalloproteinase Expression in Rats

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Abstract

Thrombin mediates the life-threatening cerebral edema and blood–brain barrier (BBB) damage that occurs after intracerebral hemorrhage (ICH). We previously found that the selective cannabinoid receptor 2 (CB2R) agonist JWH-133 reduced brain edema and neurological deficits following germinal matrix hemorrhage (GMH). We explored whether CB2R stimulation ameliorated thrombin-induced brain edema and BBB permeability as well as the possible molecular mechanism involved. A total of 144 Sprague–Dawley (S-D) rats received a thrombin (20 U) injection in the right basal ganglia. JWH-133 (1.5 mg/kg) or SR-144528 (3.0 mg/kg) and vehicle were intraperitoneally (i.p.) injected 1 h after surgery. Brain water content measurement, Evans blue (EB) extravasation, Western blot, and immunofluorescence were used to study the effects of a CB2R agonist 24 h after surgery. The results demonstrated that JWH-133 administration significantly decreased thrombin-induced brain edema and reduced the number of Iba-1-positive microglia. JWH-133 also decreased the number of P44/P42(+)/Iba-1(+) microglia, lowered Evans blue extravasation, and inhibited the elevated matrix metallopeptidase (MMP)-9 and matrix metallopeptidase (MMP)-12 activities. However, a selective CB2R antagonist (SR-144528) reversed these effects. We demonstrated that CB2R stimulation reduced thrombin-induced brain edema and alleviated BBB damage. We also found that matrix metalloproteinase suppression may be partially involved in these processes.

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Acknowledgments

We would like to thank Dr. Ya Hua from the University of Michigan for her professional comments on this research. This work was supported by grants 81571130 (Z.C) and 81070929 (Z.C) from the National Natural Science Foundation of China and 2014CB541606 (H.F) from the National Key Basic Research Development Program (973 Program) of China.

Author Contributions

ZC made substantial contributions to the conception and design. LL and YHT performed the experiments and acquired the data. JT and QWC measured the ventricular volume and cortical length. YJC and YYF participated in tissue fixation and immunohistochemistry. YY and LMY were responsible for supervising all experiments, data analysis and drafting of the manuscript. HF and GZ read and revised some parts of the manuscript. All authors read and approved the final manuscript.

Conflict of Interest

Lin Li, Yihao Tao, Jun Tang, Qianwei Chen, Yang Yang, Zhou Feng, Yujie Chen, Li Ming Yang, Yunfeng Yang, Hua Feng, and Zhi Chen declare that they have no conflicts of interest.

Compliance with Ethics Requirements

All institutional and national guidelines for the care and use of laboratory animals were followed.

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    Authors and Affiliations

    1. Department of Neurosurgery, Southwest Hospital, Third Military Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People’s Republic of China

      Lin Li, Yihao Tao, Jun Tang, Qianwei Chen, Yang Yang, Zhou Feng, Yujie Chen, Liming Yang, Gang Zhu, Hua Feng & Zhi Chen

    2. Department of Neurosurgery, Sichuan Provincial Corps Hospital, Chinese People’s Armed Police Forces, Leshan, People’s Republic of China

      Yunfeng Yang

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    1. Lin Li
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    Lin Li and Yihao Tao contributed equally to this work.

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    Li, L., Tao, Y., Tang, J. et al. A Cannabinoid Receptor 2 Agonist Prevents Thrombin-Induced Blood–Brain Barrier Damage via the Inhibition of Microglial Activation and Matrix Metalloproteinase Expression in Rats. Transl. Stroke Res. 6, 467–477 (2015). https://doi.org/10.1007/s12975-015-0425-7

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