Methylmalonate toxicity in primary neuronal cultures

摘要: Abstract Several inhibitors of mitochondrial complex II cause neuronal death in vivo and vitro . The goal the present work was to characterize effects malonate (a competitive blocker complex) which induces a pattern similar that seen striatum Huntington's disease. Exposure striatal cortical cultures from embryonic rat brain for 24 h methylmalonate, compound produces intracellularly, led dose-dependent cell death. Methylmalonate (10 mM) caused >90% mortality neurons although cells were unexpectedly more vulnerable. Cell attenuated medium containing antioxidants. Further characterization revealed DNA laddering could be detected after 3 h treatment. Morphological observations (videomicroscopy Hoechst staining) showed both necrotic apoptotic occurred parallel; apoptosis prevalent. A decrease ATP/ADP ratio observed treatment with 10 mM methylmalonate. In it concomitantly decline GABA rise aspartate content aspartate/glutamate ratio. Changes ion concentrations measured mouse brain. Neuronal [Na + ] i increased while [K membrane potential decreased 20 min continuous incubation These changes progressed time, [Ca 2+ also 1 h. results demonstrate collapses cellular gradients, restoration imposes an additional load on already compromised ATP-generation machinery. An early elevation may trigger increase activity proteases, lipases endonucleases production free radicals damage which, ultimately, leads data suggest maturational and/or extrinsic factors are likely critical vulnerability inhibition