NADPH oxidase 1, a novel molecular source of ROS in hippocampal neuronal death in vascular dementia.

Abstract

AIMS:

Chronic cerebral hypoperfusion (CCH) is a common pathological factor that contributes to neurodegenerative diseases such as vascular dementia (VaD). Although oxidative stress has been strongly implicated in the pathogenesis of VaD, the molecular mechanism underlying the selective vulnerability of hippocampal neurons to oxidative damage remains unknown. We assessed whether the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) complex, a specialized superoxide generation system, plays a role in VaD by permanent ligation of bilateral common carotid arteries in rats.

RESULTS:

Male Wistar rats (10 weeks of age) were subjected to bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]). Nox1 expression gradually increased in hippocampal neurons, starting at 1 week after 2VO and for approximately 15 weeks after 2VO. The levels of superoxide, DNA oxidation, and neuronal death in the CA1 subfield of the hippocampus, as well as consequential cognitive impairment, were increased in 2VO rats. Both inhibition of Nox by apocynin, a putative Nox inhibitor, and adeno-associated virus-mediated Nox1 knockdown significantly reduced 2VO-induced reactive oxygen species generation, oxidative DNA damage, hippocampal neuronal degeneration, and cognitive impairment.

INNOVATION AND CONCLUSION:

We provided evidence that neuronal Nox1 is activated in the hippocampus under CCH, causing oxidative stress and consequential hippocampal neuronal death and cognitive impairment. This evidence implies that Nox1-mediated oxidative stress plays an important role in neuronal cell death and cognitive dysfunction in VaD. Nox1 may serve as a potential therapeutic target for VaD.

• Authors: Dong-Hee Choi, Kyoung-Hee Lee, Ji-Hye Kim, Ju-Ha Seo, Hahn Young Kim, Chan Young Shin, Jung-Soo Han, Seol-Heui Han, Yoon-Seong Kim, Jongmin Lee
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 21 Issue 4 Pg. 533-50 (Aug 01 2014) ISSN: 1557-7716 [Electronic] United States
• PMID: 24294978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Reactive Oxygen Species
• Superoxides
• acetovanillone
• NADH, NADPH Oxidoreductases
• NADPH Oxidase 1
• NOX1 protein, rat
• rac1 GTP-Binding Protein

Topics

• Acetophenones (pharmacology)
• Animals
• Cell Death (drug effects, genetics)
• DNA Damage (drug effects)
• Dementia, Vascular (genetics, metabolism)
• Disease Models, Animal
• Gene Expression
• Hippocampus (metabolism, pathology)
• Male
• Memory (drug effects)
• NADH, NADPH Oxidoreductases (genetics, metabolism)
• NADPH Oxidase 1
• Oxidation-Reduction (drug effects)
• Oxidative Stress
• Pyramidal Cells (metabolism)
• RNA Interference
• Rats
• Reactive Oxygen Species (metabolism)
• Superoxides (metabolism)
• rac1 GTP-Binding Protein (metabolism)