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Neuroprotective Effect of JZL184 in MPP+-Treated SH-SY5Y Cells Through CB2 Receptors

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Abstract

Growing evidence suggests that the endocannabinoid system plays a role in neuroprotection in Parkinson’s disease. Recently, we have shown the neuroprotective effect of monoacylglycerol lipase (MAGL) inhibition with JZL184 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. However, further investigation is needed to determine the neuroprotective mechanisms of the endocannabinoid system on the nigrostriatal pathway. The aim of this work was to investigate whether the neuroprotective effect of JZL184 in mice could be extended to an in vitro cellular model to further understand the mechanism of action of the drug. The SH-SY5Y cell line was selected based on its dopaminergic-like phenotype and its susceptibility to 1-methyl-4-phenylpyridinium iodide (MPP+) toxicity. Furthermore, SH-SY5Y cells express both cannabinoid receptors, CB1 and CB2. The present study describes the neuroprotective effect of MAGL inhibition with JZL184 in SH-SY5Y cells treated with MPP+. The effect of JZL184 in cell survival was blocked by AM630, a CB2 receptor antagonist, and it was mimicked with JWH133, a CB2 receptor agonist. Rimonabant, a CB1 receptor antagonist, did not affect JZL184-induced cell survival. These results demonstrate that the neuroprotective effect of MAGL inhibition with JZL184 described in animal models of Parkinson’s disease could be extended to in vitro models such as SH-SY5Y cells treated with MPP+. This represents a useful tool to study mechanisms of neuroprotection mediated by MAGL inhibition, and we provide evidence for the possible involvement of CB2 receptors in the improvement of cell survival.

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Abbreviations

2-AG:

2-Arachidonoyl glycerol

AEA:

Anandamide

CB1 :

Cannabinoid type 1

CB2 :

Cannabinoid type 2

ECS:

Endocannabinoid system

FAAH:

Fatty acid amide hydrolase

MAGL:

Monoacylglycerol lipase

MPP+ :

1-Methyl-4-phenylpyridinium iodide

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

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Acknowledgments

This study was funded by the project PI14/02070 from the Spanish Government (Plan estatal I+D+I 2013–2016 and ISCIII-FEDER) and the UTE-project/Foundation for Applied Medical Research (FIMA). Estefanía Rojo-Bustamante is supported by a predoctoral fellowship from Colfuturo. We thank Oxoprobics Bioscience for the oxygen-sensing plates.

Conflict of Interest

JA Sánchez-Arias is a co-founder of Oxoprobics Bioscience.

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  1. Rafael Franco

    Present address: Department of Biochemistry and Molecular Biology, University of Barcelona, 08028, Barcelona, Spain

Authors and Affiliations

  1. Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, 31008, Spain

    María S. Aymerich & Estefanía Rojo-Bustamante

  2. Program of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pío XII 55, 31008, Pamplona, Spain

    María S. Aymerich, Carmen Molina, Marta Celorrio & Rafael Franco

  3. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain

    María S. Aymerich

  4. Small Molecules Group, Center for Applied Medical Research (CIMA), University of Navarra, 31008, Pamplona, Spain

    Juan A. Sánchez-Arias

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  1. María S. Aymerich
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Aymerich, M.S., Rojo-Bustamante, E., Molina, C. et al. Neuroprotective Effect of JZL184 in MPP+-Treated SH-SY5Y Cells Through CB2 Receptors. Mol Neurobiol 53, 2312–2319 (2016). https://doi.org/10.1007/s12035-015-9213-3

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