Tryptophan-2,3-dioxygenase-2 Inhibitors Improve Cognitive Impairment And Its Pathogenesis In Rats With Chronic Cerebral Hypoperfusion

Objective:This study assessed the effects of the tryptophan-2,3 dioxygenase 2(TDO2)inhibitor allopurinol on spatial learning and memory in rats with chronic cerebral hypoperfusion-induced cognitive impairment and whether it affects the expressions of TDO2,tryptophan,kynurenine(KYN),kynurenic acid(KYNA),or quinolinic acid(QA)in the kynurenine pathway.Methods:Adult male Sprague Dawley(SD)rats from the Animal Center of Shanxi Medical University were randomly divided into three groups: the sham operation group,the operation group,and the TDO inhibitor group.The rats in the operation group and the inhibitor group were modified by ligating bilateral common carotid arteries to create a model of chronic cerebral hypoperfusion.In the sham operation group,only tissues and blood vessels were cut and separated without ligation of the blood vessels.The Morris water maze test was used to assess the spatial learning and memory abilities of rats in each group,and the expressions of tryptophan,KYN,KYNA,and QA in the hippocampus and cerebellum of each group were detected by ELISA.The expression of TDO2 protein in the hippocampus and cerebellum was detected using the Western blot method.The detection of TDO2 mRNA expression in rats was performed with RT-PCR.Results:The results showed that,compared to the sham operation group,escape latency was prolonged on the first,second,and fifth days of the operation group,the expressions of TDO2 protein in the hippocampus and cerebellum and QA in the hippocampus increased,and the expressions of KYN,KYNA,and tryptophan did not statistically differ.Compared to the surgery group,escape latency was shortened on days 1,4,and 5 of the TDO inhibitor group,the expressions of TDO2 protein in the hippocampus and cerebellum and QA in the hippocampus were reduced,and the expression of TDO2 mRNA in the cerebellum was increased.There were no significant differences in the expressions of KYN,KYNA,or tryptophan.Conclusion:These results indicate that allopurinol can improve spatial learning and memory abilities in rats with chronic cerebral hypoperfusion,which may be achieved through a reduction in the expression of TDO2 in the hippocampus and cerebellum and the expression of QA in the hippocampus without interference with the expressions of tryptophan,KYN,or KYNA.