Sodium Taurocholatehydrate Attenuates Anesthesia/surgery-induced Cognitive Impairment With Dose-Effect Relation

Objective : Perioperative neurocognitive disorders(PND)are common postoperative complications in patients underwent surgery.They have independent adverse effects on long-term morbidity,mortality,the cost of healthcare,and quality of life.Cyclosporine A(Cs A)attenuates the isoflurane-induced mitochondrial permeability pore opening,caspase-3 activation,and impairment of learning and memory in mice.However,Cs A has immunosuppressive effects.We therefore investigate the effects of sodium taurocholatehydrate(WS635),a non-immunosuppressive Cs A analog,on the anesthesia/surgery-induced cognitive impairment in mice.The primary hypothesis is that WS635 is able to rescue the anesthesia/surgery-induced cognitive impairment in mice.Methods:Nine-month-old wild type(WT)mice were employed and subjected to abdominal surgery under 1.4% isoflurane anesthesia(anesthesia/surgery)for 2 hours.Cs A and different-dosage(13.2mg/kg,26.4mg/kg and 52.8mg/kg)WS635 were used as treatments.Barnes maze and fear conditioning test(FCT)were adopted to evaluate the cognitive function.Brain levels of postsynaptic density(PSD)-95 and Synaptophysin(SVP)was determined by western blot analysis.Brain levels of adenosine triphosphate(ATP)was measured using ELISA.Results: We found that higher-dosage(52.8mg/kg)WS635 attenuated the anesthesia/surgery-induced extension of the escape latency in Barnes maze test(P<0.05).It also increased the freezing time in the context(P<0.05)and tone(P<0.05)tests at 7 days after anesthesia/surgery in fear conditioning test.WS635 restored the PSD-95 levels in the hippocampus(P<0.05)and cortex(P<0.01),SVP levels in the cortex(P<0.05)and ATP levels in the hippocampus which were affected by anesthesia/surgery(P<0.05).Conclusion:These data suggest that WS635 could attenuate the anesthesia/surgery-induced cognitive impairment with a dose-dependent manner in mice.PSD-95 and ATP in the hippocampus might play a key role in these effects.The outcomes would promote further studies about the dose span of WS635 against the cognitive dysfunction induced by anesthesia/surgery and the potential roles of brain energy and synaptic proteins.