190 Nox2 Activation and Oxidative Damage of Cerebral Vasculature and Locomotor Function in Ageing Mice

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Abstract

Oxidative stress and oxidative damage of cerebral vasculature and neuronal cells have been found to play an important role in ageing-related neurodegenerative behaviour disorders. Although several enzymatic sources are involved in brain ROS generation, recently NADPH oxidase 2 (Nox2) has been suggested as a major source of ROS generation in ageing-related vascular dysfunction and neurodegenerative diseases. In this study, we used age-matched littermates of wild-type (WT) and Nox2 knockout (Nox2-/-) mice on a C57BL/6 background at young (3–4 month old) and old age (18–21 month old) to investigate the relationship between Nox2-derived ROS production, cerebral vascular damage and the loss of locomotor activity in ageing. There was no significant difference in locomotor activity between WT and Nox2-/- young mice as measured digitally using laser-beam motility chambers over a 42 h period. Compared to young mice, WT ageing mice (but not Nox2-/- ageing mice) had a significant decrease in horizontal activity (p < 0.05) and total activity in the dark period. We then examined the levels of ROS production in brain homogenates by lucigenin (5 µM)-chemiluminescence and in brain sections by DHE fluorescence. Compared to WT young mouse brains, there were significant increases in the levels of ROS production in WT ageing brains and this was accompanied with an average 2-fold reduction in the numbers of CD31-positive vessels (all p < 0.05) as revealed by immunofluorescence microscopy and vessel number counting. Compared to WT ageing mice, knockout of Nox2 completely inhibited the age-related increase in brain ROS production and preserved the cerebral microvasculature density and the locomotor activity. In conclusion, Nox2-derived ROS plays an important role in oxidative damage of cerebral vasculature and the loss of locomotor activity at old age.

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