Cilostazol is anti‐inflammatory in BV2 microglial cells by inactivating nuclear factor‐kappaB and inhibiting mitogen‐activated protein kinases

Abstract

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

Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways

“…Our study only demonstrated expression of TNF-α was upregulated in BV2 cells by apelin. Except for TNF-α, MIP-1α and MCP-1 have been implicated as potential modulators of the acute inflammatory response in the CNS [35]. They have potent chemoattractant capability and promote monocyte recruitment into an inflammatory or pathological site.…”

A pathophysiological role of PDE3 in allergic airway inflammation

“…However, clinical data suggest that PDE3 inhibition therapy given via infusion in heart failure, bypass operations, and enterovirus 71 infection did show antiinflammatory effects (37)(38)(39). During the last decade, a growing number of studies suggest that PDE3 inhibition might be involved in immunosuppression (40)(41)(42)(43)(44)(45)(46)(47)(48), although there is no definitive proof. There have been concerns that PDE3 inhibitors were associated with increased cardiovascular mortality in previous clinical trials (49,50).…”

Neuroprotective Compounds from Salix pseudo-lasiogyne Twigs and Their Anti-Amnesic Effects on Scopolamine-Induced Memory Deficit in Mice

“…Lev., distributed over several Asian countries, has been used for the treatment of pain and fever in Korean traditional medicine [2]. While searching for anti-inflammatory natural products using BV2 microglial cells, which are widely employed in in vitro assay systems [3,4], it was found that an 80 % methanolic extract of S. pseudo-lasiogyne significantly inhibited NO production induced by lipopolysaccharide (LPS) in BV2 microglial cells. Thus, we attempted to isolate active compounds from S. pseudo-lasiogyne and to evaluate those compoundsʼ anti-inflammatory activity in BV2 microglia.…”