1. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration.
- Author
-
Qin L, Liu Y, Hong JS, and Crews FT
- Subjects
- Aging drug effects, Animals, Brain drug effects, Brain metabolism, Chemokine CCL2 metabolism, Dopamine metabolism, Dopaminergic Neurons drug effects, Female, Interleukin-1beta metabolism, Male, Mice, Mice, Knockout, Microglia drug effects, Nerve Degeneration chemically induced, Oxidative Stress drug effects, Reactive Oxygen Species metabolism, Tumor Necrosis Factor-alpha metabolism, Aging metabolism, Dopaminergic Neurons metabolism, Lipopolysaccharides pharmacology, Microglia metabolism, NADPH Oxidases metabolism, Nerve Degeneration metabolism, Oxidative Stress physiology
- Abstract
Parkinson's disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2(+/+) ) mice with NOX subunit gp91(phox) -deficient (NOX2(-/-) ) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of TH+IR neurons in NOX2(+/+) mice, whereas NOX2(-/-) mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2(+/+) mice, but not in NOX2(-/-) mice at 1 hr. Treatment of NOX2(+/+) mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.5-6.5-fold increases in NOX2 protein (+IR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFα, IL-1β, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2(+/+) mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF