Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture

Development of progenitors in the embryonic retina is modulated by signaling molecules, and cannabinoid receptors are highly expressed in the early developing retina. Here, we investigated whether the CB1/CB2 receptor agonist WIN 5212-2 (WIN) modulated the proliferation, viability, and calcium respo...

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Bibliographic Details
Published in:	Molecular neurobiology Vol. 56; no. 9; pp. 6472 - 6486
Main Authors:	Freitas, Hércules Rezende, Isaac, Alinny Rosendo, Silva, Thayane Martins, Diniz, Geyzzara Oliveira Ferreira, dos Santos Dabdab, Yara, Bockmann, Eduardo Cosendey, Guimarães, Marília Zaluar Passos, da Costa Calaza, Karin, de Mello, Fernando Garcia, Ventura, Ana Lucia Marques, de Melo Reis, Ricardo Augusto, França, Guilherme Rapozeiro
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-09-2019 Springer Nature B.V
Subjects:	Animals Apoptosis Apoptosis - drug effects ATP Benzoxazines - pharmacology Biomedical and Life Sciences Biomedicine Calcium Calcium (intracellular) Calcium - metabolism Calcium signalling Cannabinoid CB1 receptors Cannabinoid CB2 receptors Cannabinoids - pharmacology Capsaicin Cell Biology Cell culture Cell death Cell Proliferation - drug effects Cell Survival - drug effects Cell viability Cells, Cultured Chick Embryo Embryogenesis Fatty-acid amide hydrolase Fluorescent Dyes - metabolism Glial stem cells Hydrolase Lipase Lymphocytes B Mitochondria Morpholines - pharmacology Naphthalenes - pharmacology Nestin - metabolism Neurobiology Neuroglia - cytology Neurology Neurosciences Phenotype Potassium chloride Proliferating cell nuclear antigen Receptor, Cannabinoid, CB1 - metabolism Receptor, Cannabinoid, CB2 - metabolism Receptors, Purinergic P2X7 - metabolism Retina Retina - cytology Signal Transduction - drug effects Stem Cells - drug effects Stem Cells - metabolism Sulforhodamine Superoxide Thymidine Calcium signaling Retina Endocannabinoid Müller glia ATP P2X7 receptor
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Summary:	Development of progenitors in the embryonic retina is modulated by signaling molecules, and cannabinoid receptors are highly expressed in the early developing retina. Here, we investigated whether the CB1/CB2 receptor agonist WIN 5212-2 (WIN) modulated the proliferation, viability, and calcium responses in chick embryo retinal progenitors in culture. A decline in [ 3 H]-thymidine incorporation was observed when cultures were incubated with 0.5–1.0 μM WIN, an effect that was mimicked by URB602 and URB597, inhibitors of the monoacylglycerol lipase and fatty acid amide hydrolase, respectively. A reduction in the number of proliferating cell nuclear antigen-positive nuclei was also noticed in WIN-treated cultures, suggesting that activation of cannabinoid receptors decreases the proliferation of cultured retinal progenitors. WIN (0.5–5.0 μM), but not capsaicin, decreased retinal cell viability, an effect that was blocked by CB1 and CB2 receptor antagonists and by the P2X7 receptor antagonist A438079, implicating this nucleotide receptor in the cannabinoid-mediated cell death. Treatment with WIN also induced an increase in mitochondrial superoxide and P2X7 receptor-mediated uptake of sulforhodamine B in the cultured cells. While a high proportion of cultured cells responded to glutamate, GABA, and 50 mM KCl with intracellular calcium shifts, very few cells responded to the activation of P2X7 receptors by ATP. Noteworthy, while decreasing the number of cells responding to glutamate, GABA, and KCl, treatment of the cultures with WIN induced a significant increase in the number of cells responding to 1 mM ATP, suggesting that activation of cannabinoid receptors primes P2X7 receptor calcium signaling in retinal progenitors in culture.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0893-7648 1559-1182
DOI:	10.1007/s12035-019-1537-y