Dynamics of trace element concentration during development and excitotoxic cell death in the cerebellum of Lurcher...

Elevated concentrations of Zn, Cu and Fe, observed in biopsied or post-mortem tissue from diseased human brains, have often been considered as some of the major factors in the etiology of excitotoxic neuronal death but without any direct evidence for the causal role of metals. Although elevated metal concentrations that precede or coincide with the onset of neurodegeneration may provide such evidence, the dynamics of metal concentrations during excitotoxic cell death has never been established. Hence, we measured time-resolved Zn, Cu and Fe concentrations during the course of excitotoxic cell death in the Lurcher (Lc/+) mutant mouse with neutron activation analysis. In the Lc/+ cerebellum, Fe and Zn but not Cu concentrations were substantially lower than in normal cerebellum before the onset of neurodegeneration; then the concentration of all three metals doubled during excitotoxic Purkinje cell (PC) death, before stabilizing at abnormally high levels at the end of cell death progression. The rise in metal concentrations followed the onset and progression of PC loss after a delay of almost a week. This temporal correlation between neurodegenerative progression and metal concentrations indicates that elevated metal concentrations are the consequence of metabolic overload and glial activation during excitotoxicity rather than the primary cause of PC death.