Emerging evidence indicates that astrogliosis is involved in the pathogenesis of neurodegenerative disorders. Our previous findings suggested cannabinoids and Autacoid Local Injury Antagonism Amides (ALIAmides) attenuate glial response in models of neurodegeneration. The present study was aimed at exploring palmitoylethanolamide (PEA) ability to mitigate beta-amyloid (A beta)-induced astrogliosis. Experiments were carried out to investigate PEAs (10-7M) effects upon the expression and release of pro-inflammatory molecules in rat primary astrocytes activated by soluble A beta(1-42) (1 mu g/ml) as well as to identify mechanisms responsible for such actions. The effects of A beta and exogenous PEA on the astrocyte levels of the endocannabinoidsand of endogenous ALIAmides were also studied. The peroxisome proliferator-activated receptor (PPAR)-alpha (MK886, 3 mu M) or PPAR-gamma (GW9662, 9 nM) antagonists were co-administered with PEA. A beta elevated endogenous PEA and d5-2-arachidonoylglycerol (2-AG) levels. Exogenous PEA blunted the A beta-induced expression of pro-inflammatory molecules. This effect was reduced by PPAR-alpha antagonist. Moreover, this ALIAmide, like A beta, increased 2-AG levels. These results indicate that PEA exhibits anti-inflammatory properties able to counteract A beta-induced astrogliosis, and suggest novel treatment for neuroinflammatory/ neurodegenerative processes.