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A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in
Li-Li Qiu1, Mu-Huo Ji1, Hui Zhang1
1Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Abstract:
Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2'-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1β (IL-1β), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8-OH-dG, CD11b, and IL-1β, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice.
Insights
Surgery can cause cognitive decline in aged mice by activating microglia. Inhibiting Nox2, an enzyme linked to this activation, helped prevent these effects, suggesting a potential therapeutic target for postoperative cognitive dysfunction.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Postoperative cognitive dysfunction (POCD) is a common concern, particularly in aged individuals.
- Microglial activation and subsequent neuroinflammation are implicated in POCD development.
- Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, specifically the Nox2 isoform, is a key source of reactive oxygen species (ROS) in microglia.
Purpose of the Study:
- To investigate the role of Nox2-induced microglial activation in surgery-induced cognitive impairment in aged mice.
- To explore the potential of inhibiting NADPH oxidase to mitigate these effects.
Main Methods:
- Aged mice underwent exploratory laparotomy under isoflurane anesthesia.
- Behavioral tests (open field, fear conditioning) assessed cognitive function post-surgery.
- Hippocampal and prefrontal cortex tissues were analyzed for Nox2, 8-OH-dG, CD11b, IL-1β, and BDNF levels.
- Mice were treated with the NADPH oxidase inhibitor apocynin (APO).
Main Results:
- Surgery impaired contextual fear memory and altered gene expression in the hippocampus.
- Surgery increased markers of oxidative stress (8-OH-dG) and microglial activation (CD11b, IL-1β), while decreasing BDNF.
- These changes, including neuroinflammation, persisted for 7 days in the hippocampus.
- Apocynin treatment reversed surgery-induced cognitive deficits and neuropathology.
Conclusions:
- Nox2-derived ROS in microglia contribute to surgery-induced neuroinflammation and cognitive impairment in aged mice.
- Targeting Nox2-mediated pathways may offer a therapeutic strategy for preventing POCD.
