title: Neurotoxicity of artemisinin analogs in vitro.
abstract: The sesquiterpene endoperoxide antimalarial agents arteether and artemether have been reported to cause neurotoxicity with a discrete distribution in the brain stems of rats and dogs after multiple doses. The nature and distribution of the brain lesions suggest a specific neuronal target, the identity of which is unknown. In order to further investigate artemisinin analog-induced neurotoxicity, we evaluated several in vitro models: fetal rat primary neuronal cultures, fetal rat secondary astrocyte cultures, and transformed neuronal cultures (rat-derived neuroblastoma NG108-15 and mouse-derived neuroblastoma Neuro-2a). Results indicate that toxicity was specific for neuronal cell types but not glial cells. Neurotoxicity, as indexed by liberation of lactate dehydrogenase and/or inhibition of radiolabelled-leucine uptake, was seen in all three neuronal culture types, implicating a common target. In vitro neurotoxicity was dose and time dependent. Acute exposure to drug results in delayed, but not immediate, manifestations of cell toxicity. Structure-activity comparisons indicate that substitutions at positions 9 and 10 and stereoisomerism at position 10 of the artemisinin backbone influence the degree of toxicity. The endoperoxide is necessary but not sufficient for toxicity. Sodium artesunate and dihydroartemisinin, a metabolite common to all artemisinin analogs currently being developed for clinical use, are the most potent of all analogs tested. These results are consistent with a specific neuronal target, but the identity of the target(s) remains unknown.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100.
authors.forename: D L
authors.initials: DL
authors.lastname: Wesche
authors.forename: M A
authors.initials: MA
authors.lastname: DeCoster
authors.forename: F C
authors.initials: FC
authors.lastname: Tortella
authors.forename: T G
authors.initials: TG
authors.lastname: Brewer
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000633:toxicity*; D037621:Artemisinins; D002478:Cells, Cultured; D004285:Dogs; D018698:Glutamic Acid / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D012717:Sesquiterpenes / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D018698:Glutamic Acid; C031327:artemisinin; D007770:L-Lactate Dehydrogenase