Oxidative stress in the brain at early preclinical stages of mouse scrapie.

Oxidative stress has been shown to be involved in the pathogenesis of neurodegenerative diseases including prion diseases. Although a growing body of evidence suggests direct involvement of oxidative stress in the pathogenesis of prion diseases, it is still not clear whether oxidative stress is a causative early event in these conditions or a secondary phenomenon commonly found in the progression of neurodegenerative diseases. Using a mouse scrapie model, we assessed oxidative stress in the brain at various stages of the disease progression and observed significantly increased concentration of lipid peroxidation markers, malondialdehyde and 4-hydroxyalkenals, and mRNA level of an oxidative stress response enzyme, heme oxygenase-1, at early preclinical stages of scrapie. The changes preceded dramatic synaptic loss demonstrated by immunohistochemical staining of a synaptic protein, synaptophysin. These findings imply that the brain undergoes oxidative stress even from an early stage of prion invasion into the brain. Given the well-known deleterious effects of reactive-oxygen-species-mediated damage in the brain, it is considered that the oxidative stress at the preclinical stage of prion diseases may predispose the brain to neurodegenerative mechanisms that characterize the diseases.