ABSTRACT
The transcription factor Nrf2 is a central regulator of anti-inflammatory and antioxidant mechanisms that contribute to the development and progression of various neurological disorders. Although the direct and indirect Nrf2 regulatory roles on inflammation have been reviewed in recent years, the in vivo evidence of Nrf2 function on lipopolysaccharide (LPS)-induced cognitive decline and characteristic alterations of reactive microglia and astrocytes remains incomplete. During the 3-5 days after LPS or saline injection, 5-6-month-old wildtype (WT) and Nrf2-/- C57BL/6 mice were subjected to the novel object recognition task. Immunohistochemistry staining was employed for analyses of brain cells. The Nrf2-/- mice displayed exacerbated LPS-induced cognition impairment (28.1 ± 9.6% in the discrimination index of the novel object recognition task), enhanced hippocampal reactive microgliosis and astrogliosis, and an increased expression level of the water channel transmembrane protein aquaporin 4 when compared with WT controls. In addition, similar overt effects of Nrf2 deficiency on LPS-induced characteristic alterations of brain cells were observed in the cortex and striatum regions of mice. In summary, this transgenic loss-of-function study provides direct in vivo evidence that highlights the functional importance of Nrf2 activation in regulating LPS-induced cognitive alteration, glial responses, and aquaporin 4 expression. This finding provides a better understanding of the complex nature of Nrf2 signaling and neuroprotection.
Subject(s)
Cognitive Dysfunction/metabolism , Gliosis/metabolism , Hippocampus/metabolism , Inflammation/metabolism , NF-E2-Related Factor 2/deficiency , Animals , Antioxidants/pharmacology , Cognitive Dysfunction/chemically induced , Disease Models, Animal , Lipopolysaccharides/pharmacology , Mice, Inbred C57BL , Mice, Knockout , Microglia/metabolism , NF-E2-Related Factor 2/metabolism , Neuroglia/metabolism , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: To investigate the effect of propofol and operative trauma on the neurodevelopment and cognitive function of the developing brain and its mechanism. METHODS: A total of 104 postnatal day 13 Sprague-Dawley rats were randomly divided into 4 groups: control group (treated by 7.5 mL/kg saline and sham surgery), propofol group (treated by 75 mg/kg propofol), surgery group (with abdominal surgery under local anesthesia) and propofol+surgery group (with abdominal surgery under local anesthesia plus 75 mg/kg propofol anesthesia). Thirteen rats from each group were randomly selected for detecting the content of TNF-α in the hippocampus and the expression levels of caspase-3 and c-fos in the brain. Morris Water Maze test was used to detect the cognitive ability of the other rats at 60 days old, after which TNF-α content in the hippocampus and caspase-3 and c-fos expressions in the brain were detected. RESULTS: In 13 day-old rats, TNF-α level and caspase-3 and c-fos expressions differed significantly between the surgery group and the other 3 groups (P<0.05) and were similar among the control group, propofol group and propofol+surgery group (P>0.05). In 60-day-old rats, Morris water maze test results, TNF-α level or expressions of caspase-3 and c-fos showed no significant differences among the 4 groups. CONCLUSION: Abdominal surgery can induce inflammation in the hippocampus and neuroapoptosis in neonatal rats rather than adult rats. Single-dose propofol anesthesia does not significantly affect neurodevelopment of young rats, and can relieve central inflammatory reaction induced by surgical trauma.
