Suppression of cytokine production and neural cell death by the anti-inflammatory alkaloid cepharanthine: a potential agent against HIV-1 encephalopathy.
Inflammatory cytokines and human immunodeficiency virus type 1 (HIV-1) gp120 are considered to play an important role in the pathogenesis of HIV-1-associated CNS disorders. These substances are produced predominantly by HIV-1-infected or activated macrophages and microglia in the brain and induce neural cell death. Cepharanthine is a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata and has been shown to have anti-inflammatory, anti-allergic, and immunomodulatory activities in vivo. We previously reported that this compound could inhibit tumor necrosis factor (TNF)-alpha- or phorbol 12-myristate 13-acetate-induced HIV-1 replication in latently infected U1 cells through the inhibition of nuclear factor-kappaB, a potent inducer of HIV-1 gene expression. In the present study, we demonstrated that cepharanthine suppresses the production of inflammatory cytokines and a chemokine, i.e. TNF-alpha, interleukin (IL)-1beta, IL-6, and IL-8, in human monocytic cell cultures, including primary monocyte/macrophage cultures. This effect of cepharanthine was concentration-dependent, and significant suppression was observed at 0.1 microg/mL. Furthermore, the compound also inhibited TNF-alpha- and gp120-induced death of differentiated human neuroblastoma cells at a concentration of 0.04 to 0.2 microg/mL. It penetrates the blood-brain barrier, and a medicine containing cepharanthine as a major component has been used in Japan for the treatment of patients with chronic inflammatory diseases. Thus, cepharanthine should be investigated further for its therapeutic and prophylactic potential in HIV-1-associated CNS disorders.
Okamoto
M
M
Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, 8-35-1, Sakuragaoka, 890-8520, Kagoshima, Japan.
Ono
M
M
Baba
M
M
D015526:AIDS Dementia Complex / Q000188:drug therapy*; D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044182:Benzylisoquinolines; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D052117:Benzodioxoles
D000470:Alkaloids; D000893:Anti-Inflammatory Agents; D044182:Benzylisoquinolines; D018925:Chemokines; D016207:Cytokines; C006947:cepharanthine; D052117:Benzodioxoles