Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture

Abnormalities in oxidative metabolism and inflammation accompany many neuro degenerative diseases. Thiamine deficiency (TD) is an animal model in which chronic oxidative stress and inflammation lead to selective neuronal death , whereas other cell types show an inflammatory response. Therefore, the cu rrent studies determined the response of different brain cell types to TD a nd/or inflammation in vitro and tested whether their responses reflect inhe rent properties of the cells. The cells that have been implicated in TD-ind uced neurotoxicity, including neurons, microglia, astrocytes, and brain end othelial cells, as well as neuroblastoma and BV-2 microglial cell lines, we re cultured in either thiamine-depleted media or in normal culture media wi th amprolium, a thiamine transport inhibitor. The activity levels of a key mitochondrial enzyme, a-ketoglutarate dehydrogenase complex (KGDHC), were u niquely distributed among different cell types: The highest activity was in the endothelial cells, and the lowest was in primary microglia and neurons . The unique distribution of the activity did not account for the selective response to TD, TD slightly inhibited general cellular dehydrogenases in a ll cell types, whereas it significantly reduced the activity of KGDHC exclu sively in primary neurons and neuroblastoma cells. Among the cell types tes ted, only in neurons did TD induce apoptosis and cause the accumulation of 4-hydroxy-2-nonenal, a lipid peroxidation product. On the other hand, chron ic lipopolysaccharide-induced inflammation significantly inhibited cellular dehydrogenase and KGDHC activities in microglia and astrocytes but not in neurons or endothelial cells. The results demonstrate that the selective ce ll changes during TD in vivo reflect inherent properties of the different b rain cell types.