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Targeting CB1 and GPR55 Endocannabinoid Receptors as a Potential Neuroprotective Approach for Parkinson’s Disease

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Abstract

Cannabinoid CB1 receptors (CB1R) and the GPR55 receptor are expressed in striatum and are potential targets in the therapy of Parkinson’s disease (PD), one of the most prevalent neurodegenerative diseases in developed countries. The aim of this paper was to address the potential of ligands acting on those receptors to prevent the action of a neurotoxic agent, MPP+, that specifically affects neurons of the substantia nigra due to uptake via the dopamine DAT transporter. The SH-SY5Y cell line model was used as it expresses DAT and, therefore, is able to uptake MPP+ that inhibits complex I of the respiratory mitochondrial chain and leads to cell death. Cells were transfected with cDNAs coding for either or both receptors. Receptors in cotransfected cells formed heteromers as indicated by the in situ proximity ligation assays. Cell viability was assayed by oxygen rate consumption and by the bromide-based MTT method. Assays of neuroprotection using two concentrations of MPP+ showed that cells expressing receptor heteromers were more resistant to the toxic effect. After correction by effects on cell proliferation, the CB1R antagonist, SR141716, afforded an almost full neuroprotection in CB1R-expressing cells even when a selective agonist, ACEA, was present. In contrast, SR141716 was not effective in cells expressing CB1/GPR55 heteromeric complexes. In addition, an agonist of GPR55, CID1792197, did not enhance neuroprotection in GPR55-expressing cells. These results show that neurons expressing heteromers are more resistant to cell death but question the real usefulness of CB1R, GPR55, and their heteromers as targets to afford PD-related neuroprotection.

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Funding

This study was funded by Fundació La Marató de TV3 (Grant Numbers 20141330 and 20141331).

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Author notes

  1. José Luis Lanciego and Rafael Franco contributed equally to this work.

Authors and Affiliations

  1. Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Asturias, Spain

    Eva Martínez-Pinilla

  2. Instituto de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Asturias, Spain

    Eva Martínez-Pinilla

  3. Instituto de Salud del Principado de Asturias (ISPA), Oviedo, Asturias, Spain

    Eva Martínez-Pinilla

  4. Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Diagonal 643, Prevosti Building, 08028, Barcelona, Spain

    David Aguinaga & Rafael Franco

  5. Institut de Biomedicina de la Universitat de Barcelona. IBUB, Barcelona, Spain

    David Aguinaga, Gemma Navarro & Rafael Franco

  6. Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    David Aguinaga, Gemma Navarro, Alberto J. Rico, José Luis Lanciego & Rafael Franco

  7. Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain

    Gemma Navarro

  8. Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Avenida Pío XII, 55, 31008, Pamplona, Spain

    Alberto J. Rico & José Luis Lanciego

  9. Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain

    Alberto J. Rico & José Luis Lanciego

  10. Small Molecule Discovery Platform, Molecular Therapeutics Program, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

    Julen Oyarzábal & Juan A. Sánchez-Arias

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  1. Eva Martínez-Pinilla
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Correspondence to Eva Martínez-Pinilla, José Luis Lanciego or Rafael Franco.

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Supplementary Fig. 1

MTT reduction assay in SH-SY5Y (a), SH-SY5Y-CB1R (b) and SH-SY5Y-GPR55 (c) cells treated with MPP+ (1-2 mM) for 48 h. Cell damage is represented as the percentage of MTT reduction versus control. Data are the mean ± SEM of five independent experiments. Significant differences were analyzed by a one-way ANOVA followed by post-hoc Tukey’s test. ***p < 0.001 compared with control. (PNG 332 kb)

High resolution image (TIF 68 kb)

Supplementary Fig. 2

MTT reduction assay in SH-SY5Y (a) and SH-SY5Y-CB1R/GPR55 (b) cells treated with MPP+ (1-2 mM) for 48 h. Cell damage is represented as the percentage of MTT reduction versus control. Data are the mean ± SEM of five independent experiments. Significant differences were analyzed by a one-way ANOVA followed by post-hoc Tukey’s test. ***p < 0.001 compared with control. (PNG 243 kb)

High resolution image (TIF 57 kb)

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Martínez-Pinilla, E., Aguinaga, D., Navarro, G. et al. Targeting CB1 and GPR55 Endocannabinoid Receptors as a Potential Neuroprotective Approach for Parkinson’s Disease. Mol Neurobiol 56, 5900–5910 (2019). https://doi.org/10.1007/s12035-019-1495-4

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