Abstract：
Resveratrol (RES) is a polyphenol with diverse beneficial pharmacological activities, and our previous results have demonstrated its neuroprotective potential. The purpose of this study was to investigate the therapeutic effect of RES in Alzheimer\'s disease (AD)-like behavioral dysfunction induced by streptozotocin (STZ) and explore it\'s potential mechanism of action. STZ was microinjected bilaterally into the dorsal hippocampus of C57BL/6J mice at a dose of 3 mg/kg, and RES was administered intragastrically at a dose of 25 mg/kg for 5 weeks. Neurobehavioral performance was observed, and serum concentrations of insulin and Nesfatin-1 were measured. Moreover, the protein expression of amyloid beta 1-42 (Aβ1-42), Tau, phosphorylated Tau (p-Tau) (Ser396), synaptic ras GTPase activation protein (SynGAP), postsynaptic density protein 95 (PSD95), synapsin-1, synaptogomin-1, and key molecules of the Wnt/β-catenin signaling pathway in the hippocampus and prefrontal cortex (PFC) were assessed. Finally, pathological damage to hippocampal tissue was examined by Nissl and immunofluorescence staining. The results showed that compared with the controls, bilateral hippocampal microinjections of STZ induced task-specific learning and memory impairments, as indicated by the disadvantaged performances in the novel object recognition test (NOR) and Morris water maze (MWM), but not the contextual fear conditioning test (CFC). Treatment with RES could improve these behavioral disadvantages. The serum concentrations of insulin and Nesfatin-1 in the model group were remarkably higher than those of the control group. In addition, protein expression of Aβ1-42, Tau, and p-Tau (Ser396) was increased but expression of SynGAP, PSD95, brain-derived neurotrophic factor (BDNF), and p-GSK-3β/GSK-3β were decreased in the hippocampus. Although the protein expression of BDNF and SynGAP was also markedly decreased in the PFC of the model mice, there was no significant difference among groups in the protein expression of PSD95, BDNF, synapsin-1, synaptogomin-1, and p-GSK-3β/GSK-3β. RES (25 mg/kg) reversed the enhanced insulin level, the abnormal protein expression of Aβ1-42, Tau, and p-Tau (Ser396) in the hippocampus and PFC, and the hippocampal protein expression of SynGAP, PSD95 and BDNF. In addition, RES reversed the STZ-induced decrease in the number of Nissl bodies and the increase in fluorescence intensity of IBA1 in the hippocampal CA1 region. These findings indicate that RES could ameliorate STZ-induced AD-like neuropathological injuries, the mechanism of which could be partly related to its regulation of BDNF expression and synaptic plasticity-associated proteins in the hippocampus.
摘要：
白藜芦醇（RES）是一种多酚，具有多种有益的药理活性，我们之前的结果已经证明了它的神经保护潜力。本研究的目的是研究RES在链脲佐菌素（STZ）诱导的阿尔茨海默病（AD）样行为功能障碍中的治疗作用，并探讨其潜在的作用机制。以3mg/kg的剂量将STZ双侧显微注射到C57BL/6J小鼠的背侧海马中，RES以25mg/kg的剂量胃内给药5周。观察到神经行为表现，并测定血清胰岛素和Nesfatin-1的浓度。此外，淀粉样蛋白β1-42（Aβ1-42）的蛋白表达，Tau,磷酸化Tau（p-Tau）（Ser396），突触rasGTP酶激活蛋白（SynGAP），突触后密度蛋白95（PSD95），对海马和前额叶皮质(PFC)中的突触素-1,突触素-1和Wnt/β-catenin信号通路的关键分子进行了评估.最后,通过Nissl和免疫荧光染色检查海马组织的病理损伤。结果表明,与对照组相比,双侧海马显微注射STZ诱导的任务特异性学习和记忆障碍，如新颖物体识别测试(NOR)和莫里斯水迷宫(MWM)中的不利表现所示，但不是上下文恐惧条件测试(CFC)。用RES治疗可以改善这些行为缺点。模型组血清胰岛素和Nesfatin-1浓度明显高于对照组。此外,蛋白表达Aβ1-42，Tau，和p-Tau（Ser396）增加，但SynGAP的表达，PSD95,脑源性神经营养因子(BDNF),海马中p-GSK-3β/GSK-3β降低。虽然模型小鼠PFC中BDNF和SynGAP的蛋白表达也显著降低,PSD95、BDNF、突触素-1、突触素-1和p-GSK-3β/GSK-3β。RES（25mg/kg）逆转了胰岛素水平的提高，Aβ1-42、Tau、海马和PFC中的p-Tau（Ser396），海马中SynGAP蛋白的表达,PSD95和BDNF。此外,RES逆转了STZ诱导的海马CA1区Nissl体数量的减少和IBA1荧光强度的增加。这些发现表明，RES可以改善STZ诱导的AD样神经病理损伤，其机制可能部分与其调节海马中BDNF的表达和突触可塑性相关蛋白有关。
