Effect Of Sub-anesthetic Doses Of Isoflurane And Propofol On Postoperative Cognition And Underlying Mechanism In Rats With Mild Cognitive Impairment

Objective: Mild cognitive impairment(MCI) is an intermediate stage between normal againg and Alzheimer’s disease(AD). There was a study showed that patients with MCI compared with normal individuals, patients with MCI would suffered more serious attention/concentration decline, accelerating progression to AD. Therefore, it is a great problem that anesthesiologist should concern about chosing anesthetics reasonably for patients wit MCI. Our group previously found that 2% isoflurane could increase the expressing of C/EBP homologous protein(CHOP), Cysteinyl aspartate specific proteinase(Caspase)-12 and activate caspase-3, leading to neuron apotosis, but 1% isoflurane have not effect on above index. What’s more, sub-anesthetic doses of propofol(20 mg·kg-1·h-1)could contribute to neuroprotection against ischemia/reperfusion injury, improving cognition impaired after ischemia/reperfusion injury, and maintaining the expression of potassium-chloride ion cotransporter2(KCC2), which could inverse the conversion of γ-aminobutyric acid(GABA) ergic system from inhibitory neurotransmitter system to excited transmitters system. Based on above, we adopted different anesthetics for an open tibial fracture with an intramedullary fixation under general anesthesia, in order to study the best combianation of anesthetics, further providing a new idea for anesthetics applying to patients with MCI.Methods: Two parts in our experiment. Part 1. To study the effect of sub-anesthetic doses of isoflurane and propofol on postoperative cognition in rats with MCI. MCI models: 180 Male Sprague-Dawley rats were randomly divided into model and Sham(S) group, and bilateral carotid artery was separated with no bilateral narrowing in the S group, while that was occluded in model group. After 30 d, we used Morris Water Maze to observe cognition, the proportion of the value that average escape latency minus S group escape latency in the account average escape latency <20 % was marked as MCI rats. After 36 d, MCI rats were randomly divided into 4 groups(n=12). MCI group: don’t do any processing; Isoflurane(Iso) group: 1.9% isoflurane, rats received an open tibial fracture with an intramedullary fixation, 3h; Propofol(Pro) group: 40mg·kg-1·h-1 propofol, rats received the same operation with Iso group, 3h; Combination(IP) group: 1%isoflurane+20mg·kg-1·h-1propofol, rats received rats received the same operation with Iso group, 3h. Rats in S group were only sutured skin incision. At the day 7 postoperatively, the Y maze test were evaluated to test the change of cognition, nissl staining was used to observe the surviving neurons. Part 2. To explore GABAA/KCC2 play a role in it. MCI rats were randomly divided into 4 groups(n=24). MCI group: don’t do any processing; MCI + KCC2 inhibitory: MCI rats were injected with DIOA30 μg; Combination(IP) group: the same with part1. KCC2 inhibitory+ Combination group(DIP): rats were injected with DIOA30 μg before 15 min anesthesia, doing the same operation. After 7d, Y maze was used to test cognition, immunofluorescence was adopted to observe the neurons expressing GAD67/KCC2 and western blot were applied to observe the protein level of GABAA receptor and KCC2.Results: Part1 showed the cognition and surviving neurons in MCI group were decreased compared with S group, but there were no statistically difference; IP group compared with MCI and S group respectively, cognition and surviving neurons had no difference(P>0.05). while Iso and Pro group compared with MCI group, cognition was impaired and surviving neurons was decreased(P<0.05). Part2 showed the cognition of rats in DMCIgroup was significantly impaired, besides the number of neurons expressing GAD67/KCC2 and the protein levels of GABAA receptor and KCC2 in hippocampus were decreased(P<0.05). However, the above index have no significant difference between IP group and MCI kgroup(P>0.05). While DIP group compared with IP and MCI group, cognition was impaired seriously, the number of neurons expressing GAD67/KCC2 and the protein levels of GABAA receptor and KCC2 in hippocampus were signigicantly decreased(P<0.05).Conclusion: Compared with Isoflurane(1%) and propofol(20mg·kg-1·h-1), sub-anesthetic doses of isoflurane combined with propofol has no significant effect on postoperative cognition in rats with MCI, and its mechanism is related to maintain the expression of GABAA/KCC2 pathway in hippocampal GABAergic system.