We recently described a screening system designed to detect neurotoxicity of artemisinin derivatives based on primary neuronal brain stem cell cultures (G. Schmuck and R. K. Haynes, Neurotoxicity Res. 2:37-49, 2000). Here, we probe possible mechanisms of this brain stem-specific neurodegeneration, in which artemisinin-sensitive neuronal brain stem cell cultures are compared with nonsensitive cultures (cortical neurons, astrocytes). Effects on the cytoskeleton of brain stem cell cultures, but not that of cortical cell cultures, were visible after 7 days. However, after a recovery period of 7 days, this effect also became visible in cortical cells and more severe in brain stem cell cultures. Neurodegeneration appears to be induced by effects on intracellular targets such as the cytoskeleton, modulation of the energy status by mitochondrial or metabolic defects, oxidative stress or excitotoxic events. Artemisinin reduces intracellular ATP levels and the potential of the inner mitochondrial membrane below the cytotoxic concentration range in all three cell cultures, with these effects being most dominant in the brain stem cultures. Surprisingly, there were substantial effects on cortical neurons after 7 days and on astrocytes after 1 day. Artemisinin additionally induces oxidative stress, as observed as an increase of reactive oxygen species and of lipid peroxidation in both neuronal cell types. Interestingly, an induction of expression of AOE was only seen in astrocytes. Here, manganese superoxide dismutase (MnSOD) expression was increased more than 3-fold and catalase expression was increased more than 1.5-fold. In brain stem neurons, MnSOD expression was dose dependently decreased. Copper-zinc superoxide dismutase and glutathione peroxidase, two other antioxidant enzymes that were investigated, did not show any changes in their mRNA expression in all three cell types after exposure to artemisinin.Chemically induced neurodegeneration is characterized by different patterns of neuronal cell death, gliosis, swollen or destroyed axons, or destruction of the myelin sheet. Effects on biochemical targets possibly precede manifestation of these morphologic endpoints. Therefore, not only cell viability but also integrity of the cytoskeleton and neuronal energy state should be considered (6). Primary neuronal cell cultures derived from the embryonal rat cortex have been used as a model for neuron-specific toxicity of various neurotoxicants, whose neurotoxic mode of action has been well characterized (36). The neurotoxicants include chemicals that primarily target the cytoskeleton, such as the organophosphate mipafox and ,-iminodipropionitrile, and substances that primarily impair the cellular energy supply, such as potassium cyanide and 3-nitropropionic acid. Also included were compounds such as acrylamide and 2,5-hexanedione, which act on both cytoskeleton and cellular energy production, and the well-known excitotoxin N-methyl-D-aspartate, which indirectly affects mitochondria.Artemisinin, isolated from the traditional C...
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