Background and purpose:Cilostazol is a specific inhibitor of 3′-5′-cyclic adenosine monophosphate (cAMP) phosphodiesterase, which is widely used to treat ischemic symptoms of peripheral vascular disease. Although cilostazol has been shown to exhibit vasodilator properties as well as antiplatelet and anti-inflammatory effects, its cellular mechanism in microglia is unknown. In the present study, we assessed the anti-inflammatory effect of cilostazol on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated murine BV2 microglia. Experimental approach: We examined the effects of cilostazol on LPS-induced nuclear factor-kappaB (NF-kB) activation and phosphorylation of mitogen-activated protein kinases (MAPKs). Key results: Cilostazol suppressed production of nitric oxide (NO), prostaglandin E2 (PGE2) and the proinflammatory cytokines, interleukin-1 (IL-1), tumour necrosis factor-a, and monocyte chemoattractant protein-1 (MCP-1), in a concentrationdependent manner. Inhibitory effects of cilostazol were not affected by treatment with an adenylate cyclase inhibitor, SQ 22536, indicating that these actions of cilostazol were cAMP-independent. Cilostazol significantly inhibited the DNA binding and transcriptional activity of NF-kB. Moreover, cilostazol blocked signalling upstream of NF-kB activation by inhibiting extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but without affecting the activity of p38 MAPK.
Conclusion and implications:Our results demonstrate that suppression of the NF-kB, ERK, JNK signalling pathways may inhibit LPS-induced NO and PGE2 production. Therefore, cilostazol may have therapeutic potential for neurodegenerative diseases by inhibiting pro-inflammatory mediators and cytokine production in activated microglia. (2010) 159, 1274-1285; doi:10.1111/j.1476-5381.2009.00615.x; published online 28 January 2010
British Journal of PharmacologyKeywords: cilostazol; inducible nitric oxide synthase; cyclooxygenase-2; nuclear factor-kB; monocyte chemoattractant protein-1; cAMP Abbreviations: COX-2, cyclooxygenase-2; IKK, IkB kinase; IL-1b, interleukin-1b; iNOS, inducible nitric oxide synthase; IkB, inhibitor of NF-kB; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MEKK1, MAPK/ERK kinase kinase 1; NF-kB, nuclear factor-kB; PGE2, prostaglandin E2; SEK1/MKK4, SAPK/ERK1/ MAPK kinase kinase 4; TNF-a, tumour necrosis factor-a
