The Effect Of Kynurenine 3-monooxygenase Inhibitor On The Cognitive Function Of Rats With Chronic Cerebral Hypoperfusion And Its Mechanism

Objective:To observe whether kynurenine 3-monooxygenase(KMO)inhibitors can improve the cognitive function of rats with cognitive impairment caused by chronic cerebral hypoperfusion and the expression of kynurenine pathway metabolites.Preliminarily explore the mechanism by which kynurenine 3-monooxygenase inhibitor improves the cognitive function of rats with chronic cerebral hypoperfusion cognitive impairment.Methods:After Morris water maze screening,adult healthy male SD rats were randomly divided into sham operation group,operation group,and KMO inhibitor group,15 rats in each group.Sham operation group: only skin incision was performed to find the common carotid artery without ligation(14 days for model preparation),and normal saline intragastric administration for 14 days.Operation group: Modified rat model of permanent ligation of bilateral common carotid arteries(2VO model preparation for 14 days),intragastric administration of normal saline for 14 days.KMO inhibitor group: 2VO model was prepared for 14 days,KMO inhibitor(10 mg/(kg·d))was intragastrically administered for 14 days.Then Morris water maze was used to observe the behavioral changes of rats in each group.After the behavioral test,the rats were sacrificed and the vena cava blood was taken.Western Blot was used to detect the activity of KMO in blood cells and hippocampal brain tissues of rats in each group.ELISA was used to detect the levels of tryptophan(TRP),kynurenine(KYN),kynurenic acid(KYNA),KMO,3-hydroxykynurenine(3-HK)and quinolinic acid(QUIN)in serum and hippocampal brain tissue of each group of rats.Results:In the Morris water maze test,compared with the sham operation group,the escape latency in the first 5 days of the operation group was significantly longer,and the percentage of swimming distance in the platform quadrant on the 6th day was significantly reduced(P<0.05);compared with the operation group,KMO was inhibited In the treatment group,the escape latency on days 1,2,4,and 5 was significantly shortened,and the percentage of swimming distance in the platform quadrant on the 6th day was significantly increased(P<0.05).In Western Blot detection,compared with the sham operation group,the KMO activity in blood cells and hippocampus in the operation group was significantly increased(P<0.05);compared with the operation group,the KMO activity in blood cells in the KMO inhibitor group was significantly decreased(P <0.05),there was no significant difference in KMO activity in the hippocampus(P>0.05).In the ELISA test,compared with the sham operation group,the serum and hippocampal TRP levels of the operation group decreased,and the levels of KYN,KYNA,KMO,3-HK and QUIN increased(P<0.05);compared with the operation group,KMO inhibited There was no significant difference in serum TRP and KYN levels in the drug group(P>0.05),KYNA levels increased,and KMO,3-HK and QUIN levels decreased(P<0.05);TRP,KYN,KMO and 3 in the hippocampus of the KMO inhibitor group-There was no significant difference in the level of HK(P>0.05),the level of KYNA increased,and the level of QUIN decreased(P<0.05).Conclusion:By inhibiting the activity of peripheral KMO,the cognitive function of the rat model of vascular cognitive impairment can be improved.This study found that inhibiting the activity of peripheral KMO does not affect the levels of its upstream metabolites TRP and KYN,nor does it affect the activity of KMO and 3-HK levels in the hippocampus.It is speculated that the mechanism of KMO inhibitors to improve cognitive function may be to increase the level of the neuroprotective substance KYNA in the hippocampus and reduce the level of the neurotoxic substance QUIN.