Reversal of thiamine deficiency-induced neurodegeneration

Abstract

Neurodegenerative diseases are characterized by abnormalities in oxidative processes, region- selective neuron loss, and diminished thiamine-dependent enzymes. Thiamine deficiency (TD) diminishes thiamine dependent enzymes, alters mitochondrial function, impairs oxidative metabolism, and causes selective neuronal death. In mice, the time course of TD-induced changes in neurons and microglia were determined in the brain region most sensitive to TD. Significant neuron loss (29%) occurred after 8 or 9 days of TD (TD8-9) and increased to 90% neuron loss by TD10-11. The number of microglia increased 16% by TD8 and by nearly 400% on TD11. Hemeoxygenase-1 (HO-1)-positive microglia were not detectable at TD8, yet increased dramatically coincident with neuron loss. To test the duration of TD critical for irrevocable changes, mice received thiamine after various durations of TD. Thiamine administration on TD8 blocked further neuronal loss and induction of HO-1-positive microglia, whereas other microglial changes persisted. Thiamine only partially reversed effects on TD9, and was ineffective on TD10-11. These studies indicate that irreversible steps leading to neuronal death and induction of HO-1-positive microglia occur on TD9. The results indicate that TD induces alterations in neurons, endothelial cells, and microglia contemporaneously. This model provides a unique paradigm for elucidating the molecular mechanisms involved in neuronal commitment to neuronal death cascades and contributory microglial activity.