Anti-inflammatory effects of spermidine in lipopolysaccharide-stimulated BV2 microglial cells

Background: Spermidine, a naturally occurring polyamine, displays a wide variety of internal biological activities including cell growth and proliferation. However, the molecular mechanisms responsible for its anti-inflammatory activity have not yet been elucidated. Methods: The anti-inflammatory properties of spermidine were studied using lipopolysaccharide (LPS)-stimulated murine BV2 microglia model. As inflammatory parameters, the production of nitric oxide (NO), prostaglandin E-2 (PGE(2)), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were evaluated. We also examined the spermidine's effect on the activity of nuclear factor-kappaB (NF-kappa B), and the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) pathways. Results: Pretreatment with spermidine prior to LPS treatment significantly inhibited excessive production of NO and PGE(2) in a dose-dependent manner, and was associated with down-regulation of expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Spermidine treatment also attenuated the production of pro-inflammatory cytokines, including IL-6 and TNF-alpha, by suppressing their mRNA expressions. The mechanism underlying spermidine-mediated attenuation of inflammation in BV2 cells appeared to involve the suppression of translocation of NF-kappa B p65 subunit into the nucleus, and the phosphorylation of Akt and MAPKs. Conclusions: The results indicate that spermidine appears to inhibit inflammation stimulated by LPS by blocking the NF-kappa B, PI3K/Akt and MAPKs signaling pathways in microglia.