NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration.

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.

• Authors: Liya Qin, Yuxin Liu, Jau-Shyong Hong, Fulton T Crews
• Journal: Glia (Glia) Vol. 61 Issue 6 Pg. 855-68 (Jun 2013) ISSN: 1098-1136 [Electronic] United States
• PMID: 23536230 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Chemokine CCL2
• Interleukin-1beta
• Lipopolysaccharides
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• NADPH Oxidases
• Dopamine

Topics

• Aging (drug effects, metabolism)
• Animals
• Brain (drug effects, metabolism)
• Chemokine CCL2 (metabolism)
• Dopamine (metabolism)
• Dopaminergic Neurons (drug effects, metabolism)
• Female
• Interleukin-1beta (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Knockout
• Microglia (drug effects, metabolism)
• NADPH Oxidases (metabolism)
• Nerve Degeneration (chemically induced, metabolism)
• Oxidative Stress (drug effects, physiology)
• Reactive Oxygen Species (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)