| Backgroud and objective:Postoperative cognitive dysfunction (POCD) is a common postsurgical complication. The incidence of POCD varies from 20-79% in cardiac surgery and 4.1-22.3% in non-cardiac surgery, according to data from epiderniologic studies. Researches have shown that POCD is associated with high mortality, long hospitalization, great demand of medical resources, and decreased quality of life. POCD primarily occurred in aged people, and aging is generally considered as the most crucial risk factor for the onset of POCD. Although the exact mechanism and pathophysiologic changes of POCD is largely unknown, mounting studies have shed light on the relationship between this dementia disorder and other neurodegenerative diseases. Age-related iron accumulation in brain is one of the common features of neurodegeneration. Overbalanced iron will lead to oxidative injury and excessive microglial activation, thus causing fatal damage to neurocytes. Deferoxamine (DFO), a representative iron chelator, has been used for animal models of intracerebral iron overload and neurodegenerative disorders, and has exhibited favorable prospect in clinical application.Although iron accumulation plays a crucial role in nerudegenerative diseases, the patencial mechanism of it in the development of POCD is needed to be further researched. A new day seems to be dawning for the preventative and therapeutic application of iron chelator on neurodegeneration, but the effects and mechanism of DFO on POCD have not been elucidated. Therefore, in vivo experiments were conducted to unveil how hippocampal iron accumulation impact postoperative cognition, and to explore whether DFO is effective to improve postoperative cognition, as well as its potential mechanism.Methods:1. Hippocampal iron accumulation in adult and aged rats was assessed by detecting total iron content using inductively coupled plasma mass spectrometry (ICP-MS) and by determining ferritin expression using Western blot, respectively. The impact of exploratory laparotomy on hippocampal iron accumulation was also observed.2. Morris water maze (MWM) was used to assess the impact of hippocampal iron accumulation on postoperative cognition in both adult and aged rats.3. DFO was intraperitoneally injiected before surgery. The effects on hippocampal iron accumulation and postoperative cognition were determined.4. To clarify the potential reasons of aggravated iron accumulation in hippocampus after surgery and the mechanism of improved postoperative cognition effected by DFO, the expression of proteins involved in iron transmembrane transport were detected by immunohistochemical staining (IHC) and real-time PCR; oxidative stress and anti-oxidative stress were detected by assay kits; the expression of OX-42, a marker of microglia activation, was detected by IHC; the expression of apoptosis-related proteins and in situ apoptotic cells were detected by Western blot and Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL), respectively.Results:1. Total iron content and the expression of ferritin in hippocampus were significantly increased and exacerbated after surgery in aged rats, as compared with adult rats. MWM test found that latency and distance were prolonged in aged rats after surgery, and time spent in target quadrant and central area, platform crossing time were decreased.2. Continual preoperative administration of DFO significantly reduced iron content and the expression of ferritin in hippocampus of both adult and aged rats, but the reduction was greater in aged rats than that in adult rats. Postoperative MWM test found that aged rats treated with DFO exhibited a significant lower latency and distance, more time spent in target quadrant and central area, more platform crossing time. However, no statistically significant differences were found in adult rats between DFO group and control group.3. IHC and real-time PCR showed that the expression of TfR were significantly decreased and the expression of DMT1 and hepcidin were significantly increased after surgery in aged rats. The expression of Fpnl mRNA was up-regulated, but the protein was sharply down-regulated. Although TfR level was increased by preoperatively administration of DFO, the increase of DMT 1 was inhibited. The expression of hepcidin was also inhibited by DFO treatment, thus prevented Fpnl to be reduced after surgery.4. DFO significantly inhibited the hippocampal ROS and MDA content, protected the total SOD activity, reduced the expression of OX-42 in hippocampus, inhibited the expression and activation of Caspase-3, elevated the ratio of Bcl-2/Bax by increasing Bcl-2 level and decreasing Bax level, and dramatically reduced TUNEL-positive cells in hippocampus after surgery.Conslusions:1. Age-related iron accumulation was found in hippocampus of rats. Surgical process may aggravate this pathological changes and impair postoperative cognition. Hippocampal iron accumulation may associate with postoperative cognitive decline.2. DFO may ameliorate iron accumulation and improve postoperative cognition in aged rats, but it seems that DFO is not highly effective in adult rats.3. The postoperative exacerbation of iron accumulation in hippocampus of aged rats probably due to increased iron influx and decreased efflux, caused by changes in proteins related to iron transmembrane transport.4. DFO inhibits oxidative stress and microglia activation probably through its iron-chelating activity and regulating iron transport-related proteins, by which apoptosis in hippocampus was reduced. These effects may subsequently improve postoperative cognition.5. The alleviation of hippocampal iron accumulation and improvement of postoperative cognition benefited from DFO may be a novel strategy for prevention and therapy of POCD. |
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