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Monoacylglycerol Lipase Inhibitor is Safe when Combined with Delayed r-tPA Administration in Treatment of Stroke

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Abstract

Administration of tissue plasminogen activator (tPA) during first 3–4.5 h after ischemic stroke is the main therapeutic strategy; however, its using after that, leads to reperfusion injury and neurotoxic effects. Additionally, inflammation has a critical role in secondary injury after late reperfusion therapy. Thus, this project was designed to explore the effects of JZL-184 (JZL), an agonist of type 1 cannabinoid receptor (CB1), on the side effects of recombinant tPA (r-tPA), which is administrated after 5 h of stroke onset in the mice middle cerebral artery occlusion (MCAO) model. After established the model of MCAO mouse, they were put to six groups, including intact, control, vehicle, JZL (4 mg/kg), r-tPA (9 mg/kg), and JZL plus r-tPA. Thereafter, brain levels of IL-10, TNF-α, and matrix metalloproteinase − 9 (MMP9), brain edema and infarction, and behavioral functions have been determined in the groups. JZL alone or in combination with r-tPA, but not r-tPA, reduced brain edema, infarct volume, brain levels of TNF-α, MMP9, and also improved behavioral tests. JZL and JZL plus r-tPA also increased brain levels of IL-10. According to the results, JZL can improve the effects of r-tPA to overcome stroke SSE, when used after 5 h of stroke onset. Based on the fact that there is limitation regarding using r-tPA after 3 h of stroke onset, using a combination of r-tPA/JZL can be considered for a future therapeutic strategy.

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Funding

This article is a part of Mr. Rahmani’s Ph.D. dissertation and was supported by the grant (no.: 20/1211) from the Vice Chancellor for Research and Technology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.

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Authors and Affiliations

  1. Physiology- Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Mohammad-Reza Rahmani, Ali Shamsizadeh, Elham Hakimizadeh & Mohammad Allahtavakoli

  2. Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Ali Shamsizadeh, Elham Hakimizadeh & Mohammad Allahtavakoli

  3. Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Mohammad-Reza Rahmani

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  1. Mohammad-Reza Rahmani
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  2. Ali Shamsizadeh
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  4. Mohammad Allahtavakoli
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Correspondence to Mohammad Allahtavakoli.

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Rahmani, MR., Shamsizadeh, A., Hakimizadeh, E. et al. Monoacylglycerol Lipase Inhibitor is Safe when Combined with Delayed r-tPA Administration in Treatment of Stroke. Inflammation 41, 2052–2059 (2018). https://doi.org/10.1007/s10753-018-0848-x

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  • DOI: https://doi.org/10.1007/s10753-018-0848-x

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