抑制受体相互作用蛋白1可改善慢性应激小鼠的认知功能损害

Inhibiting RIP1 improves cognitive impairments induced by chronic stress in mice

目的:检测抑制受体相互作用蛋白1(RIP1)能否改善慢性应激导致的小鼠认知功能障碍。方法:C57BL/6J雄性小鼠随机分为对照组、对照+腹腔注射necrostatin-1组(Nec-1组)、应激+腹腔注射DMSO组(应激DMSO组)、应激+腹腔注射Nec-1组(应激Nec-1组)。小鼠认知功能用旷场、新物体识别、巴恩斯迷宫评价。海马组织检测神经炎症、程序性坏死、突触可塑性、糖皮质激素受体、盐皮质激素受体。结果:与对照组相比,Nec-1组认知功能没有明显差别;应激DMSO组小鼠空间记忆能力明显下降,海马神经炎症因子IL-1α、IL-1β、TNF-α水平显著升高,p-CREB和GluA1表达明显降低,RIP1和NF-κB表达量显著升高,糖皮质激素受体和盐皮质激素受体无明显改变。给予Nec-1干预后,应激Nec-1组小鼠空间记忆改善,炎症因子IL-1α、IL-1β、TNF-α水平显著降低,RIP1和NF-κB表达量明显减少,p-CREB和GluA1表达明显增加。结论:抑制RIP1活性可显著改善慢性应激导致的小鼠脑认知功能损害及其病理改变,抑制神经炎症可能是其重要机制。

Objective:To investigate whether inhibiting receptor-interacting protein(RIP)1 by necrostatin-1 during chronic stress can improve chronic stress related brain dysfunction in mice.Methods:Healthy eight-weeks-old male C57BL/6J mice were randomly divided into four groups:control group,control+necrostatin-1(Nec-1)group,stress+DMSO group,stress+Nec-1 group.Cognitive function and movement were tested by open field,novel object recognition task and Barnes maze.The hippocampuses were collected to detect the neuroinflammation,necroptosis,neuroplasticity and the expression of glucocorticoid receptor(GR)and mineralcorticoid receptor(MR).Results:Compared with the control group,stress+DMSO group induced obvious spatial memory impairment and elevated the level of IL-1α,IL-1β,TNF-α,decreased p-CREB and GluA1 expression,and increased the contents of RIP1 and NF-κB.However,inhibiting RIP1 by Nec-1 during chronic restraint stress sufficiently rescued the spatial memory damage,suppressed the abnormal elevation of the level of IL-1α,IL-1β,TNF-α,RIP1 and NF-κB,and ameliorated the p-CREB and GluA1 depletion.Conclusion:Inhibiting RIP1 by Nec-1 can improve chronic stress related brain dysfunction by limiting neuroinflammation.