title: Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism.
abstract: Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-alpha-induced NF-kappaB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-alpha- or LPS-induced up-regulation of proinflammatory mediators, including TNF-alpha, IL-1beta, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-alpha- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-kappaB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca(2+) regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.
authors.affiliation: Aab Cardiovascular Research Institute and Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Kye-Im
authors.initials: KI
authors.lastname: Jeon
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.forename: Toru
authors.initials: T
authors.lastname: Aizawa
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Kwon
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Abe
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014748:Vinca Alkaloids / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014748:Vinca Alkaloids; C013983:vinpocetine; D051550:I-kappa B Kinase; D010727:Phosphoric Diester Hydrolases; D002118:Calcium
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