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Investigating the Effects of Exogenous and Endogenous 2-Arachidonoylglycerol on Retinal CB1 Cannabinoid Receptors and Reactive Microglia in Naive and Diseased Retina.
Papadogkonaki, Sofia; Spyridakos, Dimitris; Lapokonstantaki, Emmanouela; Chaniotakis, Nikos; Makriyannis, Alexandros; Malamas, Michael S; Thermos, Kyriaki.
Afiliación
  • Papadogkonaki S; Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece.
  • Spyridakos D; Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece.
  • Lapokonstantaki E; Department of Chemistry, University of Crete, Heraklion, 71003 Crete, Greece.
  • Chaniotakis N; Department of Chemistry, University of Crete, Heraklion, 71003 Crete, Greece.
  • Makriyannis A; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Malamas MS; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
  • Thermos K; Department of Pharmacology, School of Medicine, University of Crete, Heraklion, 71003 Crete, Greece.
Int J Mol Sci ; 24(21)2023 Oct 28.
Article en En | MEDLINE | ID: mdl-37958673
The endocannabinoid system (ECS) is a new target for the development of retinal disease therapeutics, whose pathophysiology involves neurodegeneration and neuroinflammation. The endocannabinoid 2-arachidonoylglycerol (2-AG) affects neurons and microglia by activating CB1/CB2 cannabinoid receptors (Rs). The aim of this study was to investigate the effects of 2-AG on the CB1R expression/downregulation and retinal neurons/reactive microglia, when administered repeatedly (4 d), in three different paradigms. These involved the 2-AG exogenous administration (a) intraperitoneally (i.p.) and (b) topically and (c) by enhancing the 2-AG endogenous levels via the inhibition (AM11920, i.p.) of its metabolic enzymes (MAGL/ABHD6). Sprague Dawley rats were treated as mentioned above in the presence or absence of CB1/CB2R antagonists and the excitatory amino acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Immunohistochemistry, Western blot and a 2-AG level analyses were performed. The 2-AG repeated treatment (i.p.) induced the CB1R downregulation, abolishing its neuroprotective actions. However, 2-AG attenuated the AMPA-induced activation of microglia via the CB2R, as concurred by the AM630 antagonist effect. Topically administered 2-AG was efficacious as a neuroprotectant/antiapoptotic and anti-inflammatory agent. AM11920 increased the 2-AG levels providing neuroprotection against excitotoxicity and reduced microglial activation without affecting the CB1R expression. Our findings show that 2-AG, in the three paradigms studied, displays differential pharmacological profiles in terms of the downregulation of the CB1R and neuroprotection. All treatments, however, attenuated the activation of microglia via the CB2R activation, supporting the anti-inflammatory role of 2-AG in the retina.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microglía / Endocannabinoides Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Grecia Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microglía / Endocannabinoides Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2023 Tipo del documento: Article País de afiliación: Grecia Pais de publicación: Suiza