| Background：Postoperative cognitive dysfunction (POCD) is a decline in cognitive functionespecially memory, attention after anesthesia and surgery, which has worse effect onthe quality of patient’s life and increased mortality. However, the pathogenesis ofPOCD remains unknown. Although aging is regarded as the only one clear risk ofPOCD, the causes of higher POCD morbidity in aging is still unclear. The centralcholinergic system plays an important role on regulating cognitive function such aslearning and memory. The degeneration of cholinergic system during aging coulddecrease the ability of resisting cerebral damage. Therefore, the present study aims toinvestigate whether central cholinergic degeneration is the main cause of cognitivechanges induced by surgery in aged mice, and the underlying mechanism related tonerve growth factor (NGF). This study is to provide new ideas for the prevention andtreatment of POCD.Senescence-accelerated mouse (SAM) is an inbred aging model. The SAMP-8mouse is an excellent model for studying the earliest neurodegenerative changesassociated with Alzheimer’s disease (AD). In the present study, SAMP-8mice wereused to confirm the potency of inhaled anesthetics as nontransgenic AD animalmodel, which would be helpful to optimize the anesthetic usage in AD patients.Methods and Results：1. The role of central cholinergic degeneration on surgery-induced POCD inaged miceMethods: Experiment1: To employ2-month-old and18-month-old mice undergoingappendectomy, on the third day after surgery cognitive function was assessed in aMorris water maze, and the levels of cholinergic main markers in hippocampus including choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicularacetylcholine transporter (VAChT), choline transporter (CHT) and acetylcholine(ACh)were detected by Western blot analysis and biochemical test following water mazetest. Experiment2: To verify the role of central cholinergic system on learning andmemory impairment triggered by surgery in aged mice, aged mice received donepezil(5mg/kg) in saline by intragastric administration every day for four weeks. Donepezilcould raise the activity of central cholinergic neurons. On the first day afterintragastric administration mice underwent appendectomy. Then the third day aftersurgery cognitive function was assessed in a Morris water maze, and the levels ofcholinergic main markers in hippocampus including ChAT, AChE, VAChT, CHT andACh were detected by Western blot analysis and biochemical test following watermaze test. Experiment3: To further prove the degeneration of cholinergic system isthe important cause of learning and memory impairment induced by surgery in mice,adult mice received mu-p75-saporin (0.8μg) by intracerebroventricular injection toappropriately damage the basal forebrain cholinergic neurons. Twenty days later,mice underwent appendectomy, and then cognitive function was assessed in a Morriswater maze on the third day after surgery.Results：Young adult mice showed neither a cognitive impairment on spatial learningand memory nor cholinergic dysfunction in hippocampus after surgery. In contrast,aged mice exhibited a significant deficit in spatial learning and memory and adecrease in ChAT, VAChT and ACh levels in hippocampus after surgery. Donepezilprevented surgery-induced spatial learning and memory impairment and elevatedhippocampal ACh levels in aged mice. However, we used mu-p75-saporinimmunotoxin to induce selective lesions of the basal forebrain cholinergic system inadult mice which could result in learning and memory deficit following surgery.2. The mechanism of surgey-induced central cholinergic dysfunction in agedmiceMethods: Experiment1: To investigate the effect of appendectomy on nerve growthfactor (NGF) and its maturation and degradation in aged mice，after surgery the levels of NGF, nerve growth factor precursor (proNGF), TrkA and p75NTRreceptors inhippocampus were detected by Western blot analysis. Meanwhile, the expression ofplasminogen, tissue plasminogen activator (tPA), matrix metalloproteinase9(MMP9)in hippocampus were also detected by Western blot analysis. Experiment2: To verifythe role of NGF on central cholinergic dysfunction induced by surgery in aged mice,aged mice received recombination mouse β-NGF (10μg) by bilateralintrahippocampal infusion,30minutes after infusion mice underwent appendectomy.Then the third day after surgery cognitive function was assessed in a Morris watermaze, and the levels of hippocampal cholinergic main markers including ChAT,AChE, VAChT and CHT were detected by Western blot analysis following watermaze test.Results：Surgery decreased the levels of hippocampal NGF and pTrkA receptors inaged mice, but not proNGF、p75NTRand TrkA receptors. Meanwhile, surgeryincreased the expression of MMP9, but not plasminogen and tPA. Exogenous NGFpreveted surgery-induced spatial learning and memory impairment, and reversed theimpairment of central degenerative cholinergic system induced by surgery in agedmice.3. The study of sensitivity to inhaled anesthetics in SAMP-8miceMethods: To investigate the changes of sensitivity to inhaled anesthetics, theminimum alveolar concentration (MAC) was measured by tail clamping insenescence-accelerated mouse prone-8(SAMP-8) and senescence accelerated-resistantmouse-1(SAMR-1) mice at the age of4,6,8, and10months.Results：The statistical results showed that both age and strain factors had significanteffect on the MAC values. The MAC of the SAMP-8mice was significantly lowerthan that of the SAMR-1mice for the three inhaled anesthetics. The MAC values ofthe SAMP-8mice decreased significantly with aging.Conclusion：1. The central cholinergic degeneration is the main cause of cognitive impairment induced by surgery in aged mice.2. The mechanism of surgey-induced central cholinergic impairment may be relatedto increased NGF degradation. Exogenous NGF preveted surgery-induced spatiallearning and memory impairment in aged mice.3. The SAMP-8mice were more sensitive to the three inhaled anesthetics than theSAMR-1mice. |
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