Mangiferin, a naturally occurring glucosylxanthone, has potent antioxidant and anti-inflammatory properties, as demonstrated in several reports. However, very limited information is available on the effects of this natural polyphenol on microglial activation. Thus, the aim of this study was to examine whether mangiferin is able to reduce prostaglandin E2 (PGE2) and 8-iso-prostaglandin F2α (8-iso-PGF2α) production by lipopolysaccharide (LPS)-activated primary rat microglia. Microglial cells were stimulated with 10 ng/ml of LPS in the presence or absence of different concentrations of mangiferin (1-50 μM). After 24 h incubation, culture media were collected to measure the production of PGE2 and 8-iso-PGF2α using enzyme immunoassays. Protein levels of cyclooxygenase (COX)-1 and COX-2 were studied by immunoblotting after 24 h of incubation with LPS. Mangiferin potently reduced LPS-induced PGE2 synthesis and the formation of 8-iso-PGF2α. Interestingly, mangiferin dose-dependently reduced LPS-induced COX-2 protein synthesis without modifying COX-2 transcription. This was due to a decrease in COX-2 transcript stability. However, mangiferin did not modify LPS-mediated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), a key factor involved in enhancing COX-2 mRNA stability and COX-2 translation in primary microglia. Mangiferin had no effects on LPS-induced expression of inducible nitric oxide synthase (iNOS) or TNF-α production. Taken together, results from the present study indicate that mangiferin is able to limit microglial activation, in terms of attenuation of PGE2 production, free radical formation and reduction in COX-2 synthesis induced by LPS. These data suggest that modulation of microglial activation might contribute to the mechanism of cerebral protection by mangiferin.