NLRP3炎性小体抑制剂MCC950对辐射所致认知障碍的保护作用

MCC950,a NLRP3 inflammasome inhibitor,prevents radiation-induced cognitive impairment in mice

目的探讨MCC950对辐射所致小鼠认知障碍的影响及可能机制。方法小鼠按随机数表法分为健康对照(NS)组、全身照射(IR)组和照射后MCC950干预(IR+MCC950)组,每组15只。IR组和IR+MCC950组小鼠给予137Cs单次4.0 Gy照射,吸收剂量率为1.118 Gy/min,NS组不接受照射。IR+MCC950组小鼠从照射后3周开始腹腔注射MCC950,每日1次,每次10 mg/kg。新旧事物识别等方法检测小鼠认知功能;免疫组织化学法检测小鼠海马CA3区NeuN蛋白的表达;PCR及Western blot检测NLRP3炎性小体相关蛋白的表达。结果与NS组相比,IR组小鼠短时及长期新旧事物识别指数显著降低(t=4.321、5.473,P<0.01),IR组小鼠社会认知识别指数显著降低(t=2.097,P<0.05)。MCC950治疗逆转以上改变(短时及长期新旧事物识别测验:t=5.860、4.598,P<0.05;新旧位置识别测验:t=3.040,P<0.05;社会认知测验:t=4.021,P<0.01)。IR组小鼠海马NLRP3、Caspase-1、IL-1β和IL-18的表达明显高于NS组(t=2.699、8.515、3.340、3.950,P<0.05);与NS组相比,辐射显著上调了海马BAX、Caspase-3和PARP1的表达(t=3.887、2.742、3.287,P<0.05),而MCC950显著降低了其表达(t=2.852、4.090、9.614,P<0.05)。结论NLRP3炎性小体抑制剂MCC950可能是通过降低辐射所致的海马炎症反应及神经元凋亡,从而减轻辐射所致认知损伤。

Objective To investigate the effect of MCC950(a NLRP3 inflammasome inhibitor)on cognitive impairment in mice with radiation-induced inflammatory brain injury.Methods Mice were divided into normal(NS)group,whole body irradiation(IR)group and MCC950 intervention post irradiation(IR+MCC950)group according to the random number table method,with 15 mice in each group.The mice in IR group and IR+MCC950 group were irradiated with a single dose of 4.0 Gy.The radiation source was 137Cs and the dose rate was 1.118 Gy/min.The mice in NS group were not irradiated.Mice in IR+MCC950 group were injected intraperitoneally with MCC950 once a day(10 mg/kg each time)from 3 weeks after irradiation.Behavioral tests such as new and old things recognition experiment and social cognition experiment were used to detect the cognitive function of mice.Immunohistochemistry was used to detect the expression of NeuN protein in CA3 area of mouse hippocampus.PCR and Western blot were used to detect the expression of NLRP3 inflammatory body related protein.Results Compared with NS group,the short-term and long-term recognition index of new and old things in the IR group decreased significantly(t=4.321,5.473,P<0.01),and the social cognitive recognition index of the IR group also decreased significantly(t=2.097,P<0.05).MCC950 treatment reversed the above changes(short-term and long-term new and old thing recognition test:t=5.860,4.598,P<0.05;new and old position recognition test:t=3.040,P<0.05;social cognition test:t=4.021,P<0.01).The expression of NLRP3,Caspase-1,IL-1βand IL-18 in mice hippocampus of the IR group was significantly higher than that of the control group(t=2.699,8.515,3.340,3.950,P<0.05).Compared with NS mice,radiation significantly increased the expressions of Bax,Caspase-3 and PARP1 in hippocampus(t=3.887,2.742,3.287,P<0.05),while MCC950 significantly decreased the expressions of Bax,Caspase-3 and PARP1(t=2.852,4.090,9.614,P<0.05).Conclusions NLRP3 inflammasome inhibitor MCC950 could alleviate radiation-induced cognitive impairment,which may be due to the inhibition of hippocampal inflammatory and neuronal death.