title: Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury.
abstract: BACKGROUND
  Oxidative stress is known to play an important role in the pathology of traumatic brain injury. Mitochondria are thought to be the major source of the damaging reactive oxygen species (ROS) following TBI. However, recent work has revealed that the membrane, via the enzyme NADPH oxidase can also generate the superoxide radical (O(2)(-)), and thereby potentially contribute to the oxidative stress following TBI. The current study thus addressed the potential role of NADPH oxidase in TBI.
  
  
  RESULTS
  The results revealed that NADPH oxidase activity in the cerebral cortex and hippocampal CA1 region increases rapidly following controlled cortical impact in male mice, with an early peak at 1 h, followed by a secondary peak from 24-96 h after TBI. In situ localization using oxidized hydroethidine and the neuronal marker, NeuN, revealed that the O(2)(-) induction occurred in neurons at 1 h after TBI. Pre- or post-treatment with the NADPH oxidase inhibitor, apocynin markedly inhibited microglial activation and oxidative stress damage. Apocynin also attenuated TBI-induction of the Alzheimer's disease proteins β-amyloid and amyloid precursor protein. Finally, both pre- and post-treatment of apocynin was also shown to induce significant neuroprotection against TBI. In addition, a NOX2-specific inhibitor, gp91ds-tat was also shown to exert neuroprotection against TBI.
  
  
  CONCLUSIONS
  As a whole, the study demonstrates that NADPH oxidase activity and superoxide production exhibit a biphasic elevation in the hippocampus and cortex following TBI, which contributes significantly to the pathology of TBI via mediation of oxidative stress damage, microglial activation, and AD protein induction in the brain following TBI.
authors.affiliation: Department of Neurology, Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, Georgia, United States of America.
authors.forename: Quan-Guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Laird
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Khoi
authors.initials: K
authors.lastname: Nguyen
authors.forename: Erin
authors.initials: E
authors.lastname: Scott
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Krishnan M
authors.initials: KM
authors.lastname: Dhandapani
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001929:Brain Edema / Q000201:enzymology / Q000473:pathology; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism
chemical_list: D000098:Acetophenones; D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D013481:Superoxides; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases