番茄红素调节Keap1/Nrf2/ARE信号通路对精神分裂大鼠认知障碍和氧化应激反应的影响

Effects of lycopene on cognitive impairment and oxidative stress response in schizophrenia rats by regulating Keap1/Nrf2/ARE signaling pathway

目的探究番茄红素调控Kelch样环氧氯丙烷相关蛋白1(Keap1)/核因子E2相关因子2(Nrf2)/抗氧化反应元件(ARE)通路,影响精神分裂症大鼠的氧化应激反应和认知功能。方法构建精神分裂症大鼠模型,将大鼠随机分为对照组、氯丙嗪组、模型组以及番茄红素高、低剂量组和番茄红素+Nrf2抑制剂组,每组各10例。Morris水迷宫实验检测各组大鼠认知功能;Tunel染色观察并计算各组大鼠海马组织中神经元凋亡率;酶联免疫吸附测定法(ELISA)检测大鼠血清中过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)水平;Western blotting法检测各组大鼠海马组织中Keap1、Nrf2和ARE下游抗氧化蛋白HO-1的表达水平。结果与模型组相比,番茄红素组大鼠水迷宫实验中逃避潜伏期明显缩短(2~5 d),海马组织细胞凋亡率显著降低,血清CAT、GSH-Px、SOD水平和海马组织Keap1、Nrf2、HO-1蛋白表达量显著升高(P<0.05);与番茄红素高剂量组相比,番茄红素低剂量组、番茄红素+Nrf2抑制剂组大鼠水迷宫实验中逃避潜伏期明显延长(2~5 d),海马组织细胞凋亡率显著升高,血清CAT、GSH-Px、SOD水平和海马组织Keap1、Nrf2、HO-1蛋白表达量显著降低(P<0.05)。结论番茄红素可通过调控Keap1/Nrf2/ARE通路,促进Keap1、Nrf2、HO-1的表达,缓解氧化应激,改善认知功能,从而缓解精神分裂,改善病情。

Objective To explore lycopene participates in the oxidative stress response and cognitive function of schizophrenia rats by regulating Kelch-like epichlorohydrin-related protein 1(Keap1)/nuclear factor erythroid-2 related factor 2(Nrf2)/antioxidant response element(ARE) pathway. Methods A schizophrenia rat model was constructed, and the rats were randomly divided into control group, chlorpromazine group, model group, high-dose lycopene group, low-dose lycopene group, and lycopene combined with Nrf2 inhibition group, and there were 10 cases in each group. Morris water maze test was performed to detect the cognitive function of rats in each group. Tunel staining was performed to observe and calculate the apoptosis rate of neurons in the hippocampus of rats in each group. The enzyme-linked immunosorbent assay(ELISA) was performed to measure the levels of serum catalase(CAT),glutathione peroxidase(GSH-Px), and superoxide dismutase(SOD) of rats. Western blotting methods were performed to measure the expression levels of Keap1, Nrf2, and ARE downstream antioxidant protein HO-1 in the hippocampus of rats in each group. Results Compared with the model group, the escape latency in the water maze test of the lycopene groups was significantly shortened(2 — 5d), the apoptosis rate of hippocampal cells was significantly decreased, the serum CAT, GSH-Px, SOD contents and hippocampal tissue Keap1, Nrf2, HO-1 protein expression were significantly increased(P < 0.05). Compared with the high-dose lycopene group, the lowdose lycopene group and the lycopene combined with Nrf2 inhibition group had significantly longer escape latency(2 — 5 d) in the water maze test, the apoptosis rate of hippocampal cells was significantly increased, the serum CAT, GSH-Px, and SOD contents and hippocampal tissue Keap1, Nrf2, HO-1 protein expression were significantly decreased(P < 0.05). Conclusion Lycopene can regulate the Keap1/Nrf2/ARE pathway, promote the expression of Keap1, Nrf2, and HO-1, relieve oxidative stress and ameliorate cognitive function, thereby relieving schizophrenia and improving the disease.