Effects Of ZLN005 On Hippocampal Neuroinflammation And Mitochondrial Function In Mice With Perioperative Neurocognitive Disorders

Objective To investigate the effects of ZLN005 in preventing perioperative neurocognitive disorders(PND)and to explore the potential mechanism.Methods Male C57BL/6 mice aged 7 to 8 months are randomly divided into four groups: the control group(Group C),the surgery group(Group S),the surgery and ZLN005[5 mg/(kg · d)] group(Group L),and the surgery and ZLN005[7.5 mg/(kg · d)]group(Group H).Group S,L and H were treated with isoflurane induction anesthesia and aseptic open tibial shaft fractures surgery: group S was injected with vehicle intraperitoneally once a day during the perioperative period.The corresponding dose of ZLN005 was injected intraperitoneally in group L and group H once a day during the perioperative period.Group C only received isoflurane induction anesthesia(no surgery)at the same time as the other three groups,and intraperitoneal injection of vehicle once a day during the perioperative period.The open field test,novel object recognition test and fear conditioning test were performed to measure locomotor activity,anxiety behaviors and memory of mice 6 to 9 days after operation.The levels of IL-6 and IL-1β in the hippocampus and prefrontal cortex of four groups of mice were measured by ELISA at one day after surgery.The expression levels of PGC-1α,NRF-1 in the hippocampus were detected by q-PCR at one day after surgery.The expression levels of PGC-1α,NRF-1,Atp5 d,Atp5k and Cox5 a were measured by Western blotting at three days after surgery.ATP and ROS levels were measured at 3 days after surgery.Results The total distance and anxiety behaviors of the four groups of mice in the open field test showed no statistical difference between the four groups(P > 0.05).In the new object recognition test and conditional fear test,compared with group C,the cognitive function of group S mice decreased significantly(P < 0.05).Compared with group S,the cognitive function of group L mice in the new object recognition test was significantly improved(P < 0.05).The cognitive function of group L mice in the conditional fear experiment showed an improvement trend.But there was no statistical difference(P > 0.05).Compared with group S,the cognitive function of mice in group H was significantly improved(P < 0.01).Compared with group C,the expression levels of IL-6 and IL-1β in brain tissue of group S mice were increased(P < 0.05).It suggested that surgery and anesthesia caused neuroinflammation in the mice.Compared with group S,the expression levels of IL-6 and IL-1β in the brain tissue of mice in group L and group H were decreased(P < 0.05).It indicated that ZLN005 could reduce the neuroinflammation in mice after surgery.Compared with group C mice,the expressions of PGC-1α and NRF-1 in hippocampus of group S mice were decreased(P < 0.05),the expression levels of mitochondrial respiratory chain proteins(Atp5d,Atp5 k,Cox5a)were decreased(P < 0.05),the ATP production decreased(P < 0.001),and ROS increased(P< 0.05);Compared with group S,the expressions of PGC-1α and NRF-1 in hippocampus of group L and H were increased(P < 0.05),the expression levels of mitochondrial respiratory chain proteins(Atp5d,Atp5 k,Cox5a)were increased(P <0.05),the ATP production increased,and ROS decreased(P < 0.05).Conclusions Neuroinflammation and mitochondrial damage are involved in the pathological process of PND.ZLN005 activates PGC-1α,increase the expression of mitochondrial respiratory chain proteins,improve the mitochondrial respiratory function of hippocampus,reduce the neuroinflammation,improve the cognitive damage of mice after surgery.High dose ZLN005 has a good effect on improving cognitive function in PND mice,and ZLN005 can be a potential drug for preventing PND.