PSD-95/nNOS/CAPON复合体在重复轻型颅脑损伤致神经退行性变中的作用

Role of PSD-95/nNOS/CAPON complex in neurodegeneration induced by repeated mild traumatic brain injury

目的探讨突触后致密蛋白95(PSD-95)/神经元一氧化氮合酶(nNOS)/羧基端PDZ结构域结合配体(CAPON)复合体在重复轻型颅脑损伤(rmTBI)致神经退行性变中的作用机制。方法将50只雄性C57小鼠随机分为对照组、rmTBI组、rmTBI+生理盐水组、rmTBI+抑制剂ZL006组、rmTBI+抑制剂ZLc002组,每组10只。对小鼠进行重复打击,打击完成后常规饲养1个月,模拟rmTBI损伤,rmTBI+生理盐水组、rmTBI+抑制剂ZL006组、rmTBI+抑制剂ZLc002组分别在打击前15 min腹腔注射生理盐水、抑制剂ZL006、抑制剂ZLc002。结果与对照组相比,rmTBI组小鼠出现了认知障碍和神经退行性变,并促进PSD-95/nNOS/CAPON复合体形成。使用ZL006和ZLc002可分别阻断PSD-95与nNOS、nNOS与PSD-95的相互作用,可在不改变PSD-95/nNOS/CAPON复合体组成分子蛋白表达的情况下抑制PSD-95/nNOS/CAPON复合体形成,并且改善rmTBI后的认知功能障碍。结论rmTBI促进PSD-95/nNOS/CAPON复合体形成是rmTBI后神经退行性变的重要分子病理机制,阻断其相互作用可以改善rmTBI导致的认知功能障碍,是治疗rmTBI后神经退行性变的潜在靶点。

Objective To investigate the mechanism of postsynaptic density-95(PSD-95)/neuronal nitric oxide synthase(nNOS)/carboxy-terminal PDZ ligand of nNOS(CAPON)complex in neurodegeneration induced by repetitive mild traumatic brain injury(rmTBI).Methods Fifty male C57 mice were randomly divided into control group,rmTBI group,rmTBI+saline group,rmTBI+ZL006 group,and rmTBI+ZLc002 group,with 10 mice in each group.Mice were subjected to repeated strikes,and then were routinely fed for 1 month to simulate rmTBI injury.rmTBI+saline group,rmTBI+ZL006 group and rmTBI+ZLc002 group were injected intrabitoneally with normal saline,inhibitor ZL006 and inhibitor ZLc00215 min before the strike,respectively.Results Compared with the control group,mice in the rmTBI group showed cognitive impairment and neurodegeneration,and promoted the formation of PSD-95/nNOS/CAPON complex.Blocking the interaction between PSD-95 and nNOS and between nNOS and PSD-95 using ZL006 and ZLc002,respectively,inhibited the formation of PSD-95/nNOS/CAPON complex without changing the expression of the molecular proteins that constitute PSD-95/nNOS/CAPON complex and improved cognitive dysfunction after rmTBI.Conclusion rmTBI promotes the formation of PSD-95/nNOS/CAPON complex,which is an important molecular pathological mechanism of neurodegeneration after rmTBI.Blocking their interaction can improve cognitive dysfunction caused by rmTBI,which is a potential target for the treatment of neurodegeneration after rmTBI.