Department of Physiology, Research Center of Neuroscience, Chongqing Medical University, Chongqing, 400016, China.
Neurol Sci. 2014 May;35(5):741-51. doi: 10.1007/s10072-013-1594-3. Epub 2013 Dec 12.
Recent evidence indicates that severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease pathology. It has been reported that naringenin (NAR), derived from citrus aurantium, exhibits antioxidant potential and protects the brain against neurodegeneration. The current study was designed to further investigate the protective effect of the NAR on neurodegeneration in a rat model of AD induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ), and to determine whether this neuroprotective effect was associated with brain insulin signaling. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with NAR (25, 50 mg, 100 mg/kg, respectively) for 3 weeks. The ICV-STZ injected rats did not have elevated blood glucose levels. 21 days following ICV-STZ injection, rats treated with NAR had better learning and memory performance in the Morris water maze test compared with rats treated with saline. We demonstrated that NAR increased the mRNA expression of INS and INSR in cerebral cortex and hippocampus. In addition, NAR reversed ICV-STZ induced Tau hyper-phosphorylation in both hippocampus and cerebral cortex through downregulation of glycogen synthase kinase-3β (GSK-3β) activity, a key kinase in the insulin signaling. Brain levels of Abeta, which were elevated in ICV-STZ rats, were significantly reduced in NAR-treated rats via upregulation of insulin degrading enzyme. These effects were mediated by increased insulin and insulin receptors expression in the brain, suggesting that insulin sensitizer agents might have therapeutic efficacy in early AD.
最近的证据表明，大脑葡萄糖/能量代谢和胰岛素信号的严重异常已被证明在早期散发性阿尔茨海默病病理中起着关键作用。据报道，柚皮素（NAR）来源于柑橘属植物，具有抗氧化潜力，可保护大脑免受神经退行性变的影响。本研究旨在进一步研究 NAR 对脑室注射链脲佐菌素（STZ）诱导的 AD 大鼠模型中神经退行性变的保护作用，并确定这种神经保护作用是否与大脑胰岛素信号有关。大鼠双侧脑室注射 STZ（3mg/kg），假手术大鼠给予相同体积的载体，然后分别补充 NAR（25、50、100mg/kg）3 周。脑室注射 STZ 的大鼠血糖水平没有升高。脑室注射 STZ 21 天后，NAR 治疗组大鼠在 Morris 水迷宫测试中的学习和记忆表现优于盐水治疗组大鼠。我们证明 NAR 增加了大脑皮层和海马中 INS 和 INSR 的 mRNA 表达。此外，NAR 通过下调糖原合酶激酶-3β（GSK-3β）活性逆转了脑室注射 STZ 诱导的 Tau 过度磷酸化，GSK-3β是胰岛素信号中的关键激酶。脑室注射 STZ 大鼠大脑中的 Abeta 水平升高，而 NAR 治疗组大鼠大脑中的 Abeta 水平通过上调胰岛素降解酶显著降低。这些作用是通过大脑中胰岛素和胰岛素受体表达的增加介导的，这表明胰岛素增敏剂在早期 AD 中可能具有治疗效果。
