• Cristina Benito, Rosa María Tolón, Ana Isabel Castillo, Lourdes Ruiz-Valdepeñas, José Antonio Martínez-Orgado, Francisco Javier Fernández-Sánchez, Carmen Vázquez, Benjamin F Cravatt, and Julián Romero.
• Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
• Br. J. Pharmacol. 2012 Jun 1;166(4):1474-89.

Background And PurposeThe endocannabinoid system may regulate glial cell functions and their responses to pathological stimuli, specifically, Alzheimer's disease. One experimental approach is the enhancement of endocannabinoid tone by blocking the activity of degradative enzymes, such as fatty acid amide hydrolase (FAAH).Experimental ApproachWe examined the role of FAAH in the response of astrocytes to the pathologic form of β-amyloid (Aβ). Astrocytes from wild-type mice (WT) and from mice lacking FAAH (FAAH-KO) were incubated with Aβ for 8, 24 and 48 h, and their inflammatory responses were quantified by elisa, western-blotting and real-time quantitative-PCR.Key ResultsFAAH-KO astrocytes were significantly more responsive to Aβ than WT astrocytes, as shown by the higher production of pro-inflammatory cytokines. Expression of COX-2, inducible NOS and TNF-α was also increased in Aβ-exposed KO astrocytes compared with that in WTs. These effects were accompanied by a differential pattern of activation of signalling cascades involved in mediating inflammatory responses, such as ERK1/2, p38MAPK and NFκB. PPAR-α and PPAR-γ as well as transient receptor potential vanilloid-1 (TRPV1), but not cannabinoid CB₁ or CB₂ receptors, mediate some of the differential changes observed in Aβ-exposed FAAH-KO astrocytes. The pharmacological blockade of FAAH did not render astrocytes more sensitive to Aβ. In contrast, exogenous addition of several acylethanolamides (anandamide, palmitoylethanolamide and oleoylethanolamide) induced an antiinflammatory response.ConclusionsThe genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against Aβ in a process involving PPAR-α, PPAR-γ and TRPV1 receptors.© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

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