Anti-Inflammatory Effects by Pharmacological Inhibition or Knockdown of Fatty Acid Amide Hydrolase in BV2 Microglial Cells.
Fatty acid amide hydrolase (FAAH) has been recognized as a therapeutic target for several neurological diseases because its inhibition can exert neuroprotective and anti-inflammatory effects by boosting the endogenous levels of N-acylethanolamines. However, previous studies have shown inconsistent results by pharmacological inhibition and genetic deletion of FAAH in response to inflammation. In this study we used two inhibitors, PF3845 and URB597, together with siRNA knockdown to characterize further the effects of FAAH inhibition in BV2 microglial cells. Treatment with PF3845 suppressed lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production, and down-regulated cyclooxygenase-2 and microsomal PGE synthase. PF3845 reduced the expression of pro-inflammatory cytokines but had no effect on the expression of anti-inflammatory cytokines. The anti-inflammatory effects of URB597 were not as potent as those of PF3845. Knockdown of FAAH also suppressed PGE2 production and pro-inflammatory gene expression. Interestingly, FAAH knockdown enhanced expression of anti-inflammatory molecules in both the absence and presence of LPS treatment. The anti-inflammatory effects of FAAH inhibition and knockdown were not affected by the cannabinoid receptor antagonists or the peroxisome proliferator-activated receptor (PPAR) antagonists. Although inhibition and knockdown of FAAH have potent anti-inflammatory effects and possibly lead to the dynamic change of microglial gene regulation, the underlying mechanisms remain to be elucidated.
['Tanaka|Mikiei|M|', 'Yagyu|Kazuya|K|', 'Sackett|Scott|S|', 'Zhang|Yumin|Y|']
D000581:Amidohydrolases D000818:Animals D000893:Anti-Inflammatory Agents D001549:Benzamides D002219:Carbamates D002460:Cell Line D051546:Cyclooxygenase 2 D016207:Cytokines D015232:Dinoprostone D055785:Gene Knockdown Techniques D007249:Inflammation D017628:Microglia D010880:Piperidines D011725:Pyridines
N-acylethanolamine siRNA central nervous system immune cells serine hydrolase