Oxidative Stress and Neuronal DNA Fragmentation Mediate Age-Dependent Vulnerability to the Mitochondrial Toxin, 3-Nitropropionic Acid, in the Mouse Striatum

Abstract

Oxidative stress is involved in the neuropathology of several neurodegenerative diseases and stroke, all of which are related to excitotoxicity. Age-dependent vulnerability is characteristic of these conditions. It is not clear whether apoptosis-related neuronal death is involved in age-dependent vulnerability to excitotoxicity. We evaluated whether apoptosis-related neuronal death after treatment with 3-nitropropionic acid (3-NP) is age-dependent in the mouse striatum. We have demonstrated that oxidative stress occurs early after 3-NP treatment and even more so in aged mice. DNA fragmentation with terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling staining and gel electrophoresis occurred in an age-dependent fashion. Expression of the DNA repair enzyme, apurinic/apyrimidinic endonuclease, was more attenuated in old mice. Therefore, these results suggest that oxidative stress induces age-dependent neuronal apoptosis in the mouse striatum after 3-NP treatment, which in turn produces an age-dependent vulnerability to 3-NP.