title: Inhibition of intracellular proliferation of Leishmania parasites in vitro and suppression of skin lesion development in BALB/c mice by a novel lipid A analog (ONO-4007).
abstract: A synthetic lipid A analog (ONO-4007) exhibits antileishmanial activity by activating Leishmania-infected macrophages in experimental leishmaniasis. In the present in vitro study, ONO-4007 at concentrations between 0.01 and 1.00 mg/mL markedly inhibited the proliferation of Leishmania major and L. amazonensis promastigotes. Ultrastructurally, L. major-infected macrophages showed degenerated intracellular amastigotes after exposure to ONO-4007. Leishmania-infected macrophages treated with ONO-4007 showed poorly developed parasitophorous vacuoles. High levels of tumor necrosis factor-alpha were induced by ONO-4007 in Leishmania-infected macrophages. In this in vivo study, L. amazonensis-infected BALB/c mice were treated with a dose of 30 mg/kg of ONO-4007 by perilesional and peritoneal injections. The skin lesion size was assessed before treatment with ONO-4007 and at eight weeks after injection. The lesion size was significantly suppressed in mice perilesionally injected with ONO-4007 (P < 0.01) compared with the controls. The data from our present in vitro and in vivo studies indicate that ONO-4007 has an antileishmanial effect.
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. k998761@med.u-ryuku.ac.jp
authors.forename: Mohammed A K
authors.initials: MA
authors.lastname: Khan
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Maruno
authors.forename: Noor M
authors.initials: NM
authors.lastname: Khaskhely
authors.forename: Saeef T
authors.initials: ST
authors.lastname: Ramzi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosokawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uezato
authors.forename: Eduardo A Gomez
authors.initials: EA
authors.lastname: Landires
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Hashiguchi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nonaka
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development* / Q000648:ultrastructure; D018320:Leishmania major / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000981:Antiprotozoal Agents; D008050:Lipid A; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha