Pharmacological blockade of fatty acid amide hydrolase (FAAH) by URB597 improves memory and changes the phenotype of hippocampal microglia despite ethanol exposure

Rivera, Patricia; Fernández Arjona, María del Mar; Silva Peña, Daniel; Blanco Calvo, Eduardo; Vargas, Antonio; López Ávalos, María Dolores; Grondona, Jesús M.; Serrano, Antonia; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Suárez, Juan

doi:https://doi.org/10.1016/j.bcp.2018.08.005

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2018

Author

Rivera, Patricia

Fernández Arjona, María del Mar

Silva Peña, Daniel

Blanco Calvo, Eduardo

Vargas, Antonio

López Ávalos, María Dolores

Grondona, Jesús M.

Serrano, Antonia

Pavón, Francisco Javier

Rodríguez de Fonseca, Fernando

Suárez, Juan

Suggested citation

Rivera, Patricia; Fernández Arjona, María del Mar; Silva Peña, Daniel; Blanco Calvo, Eduardo; Vargas, Antonio; López Ávalos, María Dolores; ... Suárez, Juan. (2018) . Pharmacological blockade of fatty acid amide hydrolase (FAAH) by URB597 improves memory and changes the phenotype of hippocampal microglia despite ethanol exposure. Biochemical Pharmacology, 2018, vol. 157, p. 244-257. https://doi.org/10.1016/j.bcp.2018.08.005.

Abstract

Changes in endogenous cannabinoid homeostasis are associated with both ethanol-related neuroinflammation and memory decline. Extensive research is still required to unveil the role of endocannabinoid signaling activation on hippocampal microglial cells after ethanol exposure. Either microglial morphology,

phenotype and recruitment may become notably altered after chronic alcohol-related neurodegeneration. Here, we evaluated the pharmacological effects of fatty-acid amide-hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg), oleoylethanolamide (OEA, 10 mg/kg), arachidonoylethanolamide (AEA, 10 mg/kg), the CB1 receptor agonist ACEA (3 mg/kg) and the CB2 receptor agonist JWH133 (0.2 mg/kg) administered for 5 days in a rat model of subchronic (2 weeks) ethanol diet (11% v/v) exposure. URB597 turned to be the most effective treatment. URB597 increased microglial (IBA-1+) cell population, and changed morphometric features (cell area and perimeter, roughness, fractal dimension, lacunarity) associated with activated microglia in the hippocampus of ethanol-exposed rats. Regarding innate immune activity, URB597 specifically increased mRNA levels of toll-like receptor 4 (TLR4), glial fibrillary acidic protein (Gfap) and the chemokine stromal cell-derived factor 1 (SDF-1α/CXCL12), and elevated the cell population expressing the chemokine receptors CX3CR1, CCR2 and CCR4 in the ethanol-exposed rat hippocampus. Contrary to ethanol effect, URB597 reduced mRNA levels of Iba-1, Tnfα, IL-6 and the monocyte chemoattractant protein-1 (MCP-1/CCL2), as well as cell population expressing iNOS. URB597 effects on hippocampal immune system were accompanied by changes in short and long-term visual recognition memory. These results suggest that FAAH inhibition may modulates hippocampal microglial recruitment and activation that can be associated with improved hippocampal-dependent memory despite ethanol exposure.

URI

http://hdl.handle.net/10459.1/65392

DOI

https://doi.org/10.1016/j.bcp.2018.08.005

Is part of

Biochemical Pharmacology, 2018, vol. 157, p. 244-257

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Publicacions de projectes de recerca del Plan Nacional [2035]
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Except where otherwise noted, this item's license is described as cc-by-nc-nd (c) Elsevier, 2018