吲哚胺2,3-二加氧酶抑制剂对慢性脑低灌注大鼠认知功能损害的行为学改善

Effect of indoleamine 2,3-dioxygenase inhibitors on cognitive impairment in rats with chronic cerebral hypoperfusion

目的观察使用吲哚胺2,3-二加氧酶(IDO)抑制剂后慢性脑低灌注大鼠认知功能损害的行为学改善,及血犬尿氨酸(KYN)、犬尿喹啉酸(KYNA)水平的变化。方法雄性Wistar大鼠30只,随机分为假手术组,对照组和IDO抑制剂组,各10只,后2组采用改良的永久性双侧颈总动脉结扎术制作慢性脑低灌注大鼠模型。Morris水迷宫检测大鼠空间学习与记忆能力变化,高效液相色谱-荧光检测法检测血KYN、KYNA的水平,免疫组织化学检测大鼠海马CA1区IFN-γ、TNF-α表达。结果与假手术组比较,对照组IFN-γ、TNF-α表达明显升高(P<0.05);与对照组比较,IDO抑制剂组大鼠第4、5天逃避潜伏期缩短,平台象限游泳距离百分比增加,KYN[(15.33±0.90)μmol/L vs(1.69±0.94)μmol/L]及KYNA[(39.51±3.81)μmol/L vs(25.66±6.80)μmol/L]水平明显降低(P<0.05),但IFN-γ、TNF-α表达无显著差异(P>0.05)。结论 IDO抑制剂不影响炎性因子表达,但可减少血KYN及KYNA表达,可改善慢性脑低灌注所致的认知功能损害的空间学习及记忆能力。

Objective To study the effect of IDO inhibitors on serum KYN and KYNA level,expression of IFN-γand TNF-α,and cognitive impairment in rats with chronic cerebral hypoperfusion.Methods Thirty male Wistar rats were randomly divided into sham operation group,control group and IDO inhibitor group（10in each group）.A rat chronic cerebral hypoperfusion model was established by permanent ligation of bilateral common carotid arteries.The spatial learning and memory ability of rats was tested by Morris water maze test.The serum KYN and KYNA levels were measured by high-performance liquid chromatography-fluorescence assay.Expressions of IFN-γand TNF-αin hippocampal CA1 were detected by immunohistochemistry.Results The expression levels of IFN-γand TNF-αwere significantly higher in control group than in IDO inhibitor group（P〈0.05）.The escape incubation period and platform quadrant swimming distance were significantly shorter and the serum KYN and KYNA levels were significantly lower in IDO inhibitor group than in control group（P〈0.05）.However,no significant difference was found in expression levels of IFN-γand TNF-αbetween the two groups（P〉0.05）.Conclusion IDO inhibitors have no effect on expression of inflammatory cytokines.However,they can reduce the synthesis of serum KYN and KYNA,and improve the spatial learning and memory ability in patients with cognitive impairment due to chronic cerebral hypoperfusion.