In vitro neurotoxicity of artemisinin derivatives

The known neurotoxicity of high doses of arteether and dihydroartemisinin in experimental animals has led to the need for a rapid screening method to predict the potential neurotoxicity of newly developed artemisinin-related antimalarial drugs. We have studied the effects of a range of these compounds on the neurite outgrowth of differentiating NB2a neuroblastoma cells in vitro, an assay that shows a correlation with neurotoxicity in vivo for a range of neurotoxic agents. In this assay, dihydroartemisinin is significantly more toxic than artemether or arteether. In the presence of liver metabolising enzymes, in vitro neurotoxicity of artemether and arteether is markedly increased. Differentiated neuronal cells are more sensitive than differentiated glial cells. Electron microscopy confirms that the targets in the neuronal cell for dihydroartemisinin are mitochondrial membranes and endoplasmic reticulum. The technique forms a valuable component of a range of appropriate neurotoxicity screening tests that should continue to be applied to newly developed antimalarials of this type.