| First Author | Benito C | Year | 2012 |
| Journal | Br J Pharmacol | Volume | 166 |
| Issue | 4 | Pages | 1474-89 |
| PubMed ID | 22321194 | Mgi Jnum | J:322090 |
| Mgi Id | MGI:6836943 | Doi | 10.1111/j.1476-5381.2012.01889.x |
| Citation | Benito C, et al. (2012) beta-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-alpha, PPAR-gamma and TRPV1, but not CB(1) or CB(2) receptors. Br J Pharmacol 166(4):1474-89 |
| abstractText | 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 beta-amyloid (Abeta). Astrocytes from wild-type mice (WT) and from mice lacking FAAH (FAAH-KO) were incubated with Abeta 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 Abeta than WT astrocytes, as shown by the higher production of pro-inflammatory cytokines. Expression of COX-2, inducible NOS and TNF-alpha was also increased in Abeta-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 NFkappaB. PPAR-alpha and PPAR-gamma as well as transient receptor potential vanilloid-1 (TRPV1), but not cannabinoid CB(1) or CB(2) receptors, mediate some of the differential changes observed in Abeta-exposed FAAH-KO astrocytes. The pharmacological blockade of FAAH did not render astrocytes more sensitive to Abeta. 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 Abeta in a process involving PPAR-alpha, PPAR-gamma and TRPV1 receptors. |
