| Objectives: Alzheimer's disease?AD? is the most common form of dementia and is characterized by a progressive cognitive impairment, emotion changes and abnormal behavior. As Chinese aging society is coming, the morbidity of AD rises rapidly, which risk the health and life of old people. So far, the pathogenesis of AD is still not completely clear and there are no effective treatments to reverse it. Because of the failure of novel drug's clinical trials, the therapeutic of AD comes to a standstill and developing new drugs becomes socially research hotspot which attracted much attention.Although the precise pathogenesis of AD is still unknown, increasing evidence indicates that the oxidative stress injury caused by excessive deposition of ?-amyloid protein in the brain plays an important role in promoting AD. The free radicals and reactive oxygen species produced in this pathological process can attack proteins, nucleic acids and biological membrane,leading to mitochondrial dysfunction, calcium overload and even apoptosis. Silent mating type information regulation homolog1?sirt1? is a kind of antioxidant genes found in recent years, which plays an important biological functions in transcriptional regulation. Nrf2/ARE is currently acknowledged as a defensive transduction pathway which can resistance to the internal and external stimulation of oxidation and chemical by activating gene transcription and expression such as two phase detoxifying enzymes, antioxidants, protease and molecular chaperone. Some research shows that Sirt1 can promote the activation of Nrf2/ARE antioxidant pathway by influencing the transcription activity of Nrf2. In the early stages of AD, the lever of Sirt1 and Nrf2 are increased to resist harmful stimulus. While with the progress of AD, the lever of them both have a significant reduction,which resulting in a further reduction of oxidative stress resistance. Therefore, enhancing the antioxidant capacity is a potential therapeutic strategy for AD.For the past few years, researchers had a lot of study to treat AD with the active components of natural medicine, so as to find effective medicines. Xanthohumol, which is extracted from hops, has been shown to possess the pothential neuroprotective effect and is expected to be an useful drug for the prevention and treatment of AD. However, so far, it is uncertain whether Xn can attenuate cognitive function impairment and oxidative stress in AD rat. In this study, we builded the AD rats model by bilateral hippocampus injection of A?1-42 and observe the rats behavior changes, histopathological changes of the hippocampal neurons, oxidative stress status and the expression of Sirt1, Nrf2 and HO-1 in the rat hippocampus. Based on these data, the current study investigated the effects of Xn on A?1-42-induced oxidative stress and cognitive dysfunction. Furthermore, the potential roles of Sirt1 and Nrf2 in this progress were also illustrated.Methods: sixty healthy male SD rats?250±50g? were randomly assigned to five groups?n=12 for each group? according to the random figure chart: Sham group, Sham+Xn group, A?1-42 group, A?1-42+Xn group and A?1-42 + Res group. The study was performed after the rats were allowed to acclimate for one week. The Sham+Xn group and A?1-42+Xn group were treated Xn by intravenous injection once a day. The A?1-42 + Res group were treated Res by intraperitoneal injection and other groups were treated with equal solvent once a day. After three weeks, the A?1-42 group, A?1-42+Xn and A?1-42+Res group were injected into the rats' bilateral hippocampus with 10?g A?1-42, and the other two groups with equal solvent. Rats were administered by intravenous injection with Xn(Sham+Xn group and A?1-42+Xn group), intraperitoneal injection with Res(A?1-42+Res group) and solvent(Sham group and A?1-42 group) for 12 days after the injection of hippocampus.And then learning and memory abilities of each group rats were detection through morris water maze test. HE staining was adopted to observe the pathological changes of hippocampus CA1 area neurons. Using spectrophotometry to detect the SOD activity and MDA content. The expression and localization of Sirt1, Nrf2,HO-1 were analyzed by western blot and immunohistochemistry.Results:1 Morris water maze test: The result showed that each group's escape latent period was not same and the number through the platform was also disparate. The escape latency of A?1-42 group was significantly increased compared with sham group?P<0.05?, while A?1-42+Xn group and A?1-42+Res group showed obviously improvements compared with A?1-42 group?P<0.05?. The number of platform crossings by the A?1-42+Xn rat was significantly higher that of AD rat. However, the escape latent period and the number of through the platform of A?1-42+Xn group did not show obvious differences compared with the A?1-42+Res group.2 HE staining: Membrane shrinkage, nucleus pyknotic and intensive blue-stain in cell body were observed in the degenerated cells in the hippocampal CA1 region. The Sham and Sham+Xn group had only a small amount of the degenerated neurons. However, the number of degenerated neurons in the A?1-42 group increased obviously. Treatment with Xn or Res both significantly reduced the number of degenerated neurons. The morphology and structure of the neurons had different degrees of recovery.3 Xn attenuated A?1-42-induced oxidative stress of the hippocampal tissue: Compared with the Sham group, The activity of SOD decreased sharply and the content of MDA increased significantly?P<0.05?. The A?1-42+Xn and A?1-42+Res group was significantly relieved the above phenomenon and there were no significant differences between them?P>0.05?.4 Xn upregulated the expression of Sirt1, Nrf2 and HO-1: Compared with the Sham group, the number of positive cells and expression levers of Sirt1, Nrf2 and HO-1 decreased significantly in the A?1-42 group?P<0.05?. The A?1-42+Xn group was significantly increased the number of positive cell and expression levers of the above indexes compared with A?1-42 group?P<0.05?, and there were no significantly differences compared with the A?1-42+Res group?P>0.05?.Conclusions:1 The injection of A?1-42 into rat bilateral hippocampus provides an effective model to mimic some of the pathologic and behavioral changes of AD.2 Hippocampal SOD activity was attenuated but MDA levels were increased by A?1-42 treatment which finally promote neuron degeneration. Simultaneously, The protein expression of Sirt1, Nrf2 and HO-1 in the hippocampal CA1 areas were also declined, which indicated oxidative stress play a pivotal role in the generation and development of AD.3.Xn effectively improved the learning and memory abilities of the AD rats and reduced the number of the degenerated neurons, which testified the neuroprotective effect of it. There were no significantly differences in the neuroprotective effect between Xn and Res.4.Xn improved the anti-oxidative capacity of the hippocampals of the AD rats, which performanced on heightened the SOD activity and reduced the MDA content. The protein expression of Sirt1, Nrf2 and HO-1 were also significantly upregulated, which prompted that the neuroprotective effect of Xn may closely associated with its activation of Sirt1-Nrf2-HO-1 pathway. |
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