Background:

Bindarit(AF-2838), an anti-inflammatory agent, is a selective inhibitor againstmonocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7 and MCP-2/CCL8[1].

MCP-1, MCP-2, and MCP-3 are inflammatory mediators that specifically stimulate the directional migration of T cells as well as monocytes and may play an important role in immune cell recruitment into sites of antigenic challenge [2].

In vitro: Bindarit inhibited MCP-1 and TNF-alpha production induced in monocytes by LPS and Candida albicans in a dose-dependent manner with the IC50 of 172 μM and 403 μM, respectively.The inhibition of LP-induced MCP-1 production by Bindarit has been associated with the reduced levels of MCP-1 mRNA transcripts with the IC50 value of 75 μM. Bindaritexihibited an inhibitory effect in the production of MCP-1 by LPS-stimulated MM6 cells with an IC50 of 425 μM, without affecting the release of IL-8 or IL-6[3].Administration of bindarit (10-300 μM) reduced rat vascular smooth muscle cell (VSMC) proliferation, migration, and invasion[4].

In vivo: In NZB/W mice model with lupus nephritis, oral treatment of bindarit prolonged survival and delayed the onset of proteinuria [3]. In rats treated with bindarit (200 mg/kg/day), bindarit resulted in a 39% reduction of balloon injury-induced neointima formation at day 14 without affecting re-endothelialization. Bindarit reduced the number of medial and neointimal proliferating cells at day 7 by 54 and 30%, respectively. In hypercholesterolaemicapoE(-/-) mice, administration of bindarit reduced the number of proliferating cells by 42%at day 7 after carotid injury and inhibited of neointima formation by 47% at day 28. In neointimal lesions of apoE(-/-) mice treated with bindarit, data analysis of the cellular composition showed that the relative content of macrophages and the number of VSMCs were reduced by 66 and 30%, respectively, compared with the control group[4].

参考文献:
[1]. Zoja C, Corna D, Benedetti G, et al. Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease[J]. Kidney international, 1998, 53(3): 726-734.
[2]. Taub D D, Proost P, Murphy W J, et al. Monocyte chemotactic protein-1 (MCP-1),-2, and-3 are chemotactic for human T lymphocytes[J]. Journal of Clinical Investigation, 1995, 95(3): 1370.
[3]. Sironi M, Guglielmotti A, Polentarutti N, et al. A small synthetic molecule capable of preferentially inhibiting the production of the CC chemokine monocyte chemotactic protein-1[J]. European cytokine network, 1999, 10(3): 437-442.
[4]. Grassia G, Maddaluno M, Guglielmotti A, et al. The anti-inflammatory agent bindarit inhibits neointima formation in both rats and hyperlipidaemicmice[J]. Cardiovascular research, 2009, 84(3): 485-493.