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Unique Effects of Compounds Active at Both Cannabinoid and Serotonin Receptors During Stroke

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Abstract

We reported previously that both a cannabinoid receptor 2 (CB2R) agonist and a cannabinoid receptor 1 (CB1R) antagonist were protective in the treatment of transient middle cerebral artery occlusion/reperfusion injury (MCAO/R) and that they acted in a synergistic manner when administered in combination. The goal of the current study was to determine which of the potential cannabinoid receptors participate in the protective effects of this drug combination in a mouse model of MCAO/R. The effects of administration of the CB2R agonist/CB1R antagonist combination on infarct size and cerebral blood flow during a 1-h occlusion were tested in CB1R-deficient animals, CB2R-deficient animals, and animals treated with capsazepine, the antagonist for the vanilloid receptor type I (TRPV1) and WAY100135, the antagonist for the hydroxytryptamine1A receptor (5-HT1A). The protective effect of the CB2R agonist/CB1R antagonist combination on infarct size was not influenced by the absence of the CB1R nor by blocking the TRPV1 receptor, but was attenuated by the absence of CB2R and by blocking the 5-HT1A receptor. Increases in cerebral blood flow and arteriolar diameter were also found to be independent of the CB1R and TRPV1 receptor. In conclusion, administration of the CB2R agonist/CB1R antagonist combination causes a significant reduction in infarct size in the MCAO/R model. The protective effect involves both the CB2R and the 5-HT1A receptor. Neither the CB1R nor the TRPV1 receptors appear to participate in this response.

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Acknowledgments

This project was supported, in part, by grants 1RO1AI084065 (DG and RFT), DA P30 13429 (DG, RFT, and MZ), DA005488 (AM and MA), and DA009789 (AM and MA) from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pathology, Temple University School of Medicine, Philadelphia, PA, USA

    Ming Zhang

  2. Organix, Inc., Woburn, MA, USA

    Anu Mahadevan & Mukkanti Amere

  3. Department of Physiology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA

    Hongbo Li & Ronald F. Tuma

  4. Department of Microbiology and Immunology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA

    Doina Ganea

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  1. Ming Zhang
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  2. Anu Mahadevan
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Correspondence to Ronald F. Tuma.

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Zhang, M., Mahadevan, A., Amere, M. et al. Unique Effects of Compounds Active at Both Cannabinoid and Serotonin Receptors During Stroke. Transl. Stroke Res. 3, 348–356 (2012). https://doi.org/10.1007/s12975-012-0197-2

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  • DOI: https://doi.org/10.1007/s12975-012-0197-2

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