Document Detail


β-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-α, PPAR-γ and TRPV1, but not CB₁ or CB₂ receptors.
MedLine Citation:
PMID:  22321194     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: The 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 APPROACH: We 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 RESULTS: FAAH-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.
CONCLUSIONS: The genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against Aβ in a process involving PPAR-α, PPAR-γ and TRPV1 receptors.
Authors:
Cristina Benito; Rosa María Tolón; Ana Isabel Castillo; Lourdes Ruiz-Valdepeñas; José Antonio Martínez-Orgado; Francisco Javier Fernández-Sánchez; Carmen Vázquez; Benjamin F Cravatt; Julián Romero
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  166     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-18     Completed Date:  2012-10-09     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1474-89     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
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MeSH Terms
Descriptor/Qualifier:
Amidohydrolases / antagonists & inhibitors,  genetics,  metabolism*
Amyloid beta-Peptides / metabolism*
Animals
Animals, Newborn
Astrocytes / cytology,  drug effects,  immunology*,  metabolism
Cells, Cultured
Cyclooxygenase 2 / genetics,  metabolism
Cytokines / metabolism
Enzyme Inhibitors / pharmacology
Gene Expression Regulation / drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins / agonists,  antagonists & inhibitors,  genetics,  metabolism
Neurons / cytology,  drug effects,  immunology*,  metabolism
Nitric Oxide Synthase Type II / genetics,  metabolism
PPAR alpha / agonists,  genetics,  metabolism*
PPAR gamma / agonists,  genetics,  metabolism*
Peptide Fragments / metabolism*
RNA, Messenger / metabolism
Receptor, Cannabinoid, CB1 / antagonists & inhibitors,  genetics,  metabolism
Receptor, Cannabinoid, CB2 / antagonists & inhibitors,  genetics,  metabolism
TRPV Cation Channels / antagonists & inhibitors,  genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Cnr2 protein, mouse; 0/Cytokines; 0/Enzyme Inhibitors; 0/Nerve Tissue Proteins; 0/PPAR alpha; 0/PPAR gamma; 0/Peptide Fragments; 0/RNA, Messenger; 0/Receptor, Cannabinoid, CB1; 0/Receptor, Cannabinoid, CB2; 0/TRPV Cation Channels; 0/TRPV1 protein, mouse; 0/amyloid beta-protein (1-42); EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nos2 protein, mouse; EC 1.14.99.-/Ptgs2 protein, mouse; EC 1.14.99.1/Cyclooxygenase 2; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase
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