異鉤藤堿抗阿爾茨海默病:基於兩個阿爾茨海默病小鼠模型的實驗研究 (Exploring Isorhynchophylline as an Anti-Alzheimer’s Disease Agent Using two animal models: Its Efficacy and Action Mechanisms)
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AbstractBackground: Alzheimer’s disease (AD) is the most common form of dementia in elderly people with huge health and economic burden to the society. So far, the treatment for AD is largely unsatisfactory. Isorhynchophylline (IRN) is a c-22 oxindole alkaloid that was isolated from Uncaria. rhynchophylla (Gou-Teng in Chinese). Recent studies in our laboratory have shown that IRN has potent neuroprotective effects in different in vivo and in vitro models of AD. To provide more scientific rationale and justification for future clinical study on this anti-AD alkaloid, the present project aimed to investigate the cognitive deficit ameliorating effects of IRN on aluminum chloride (AlCl3)-induced AD model and TgCRND8 transgenic mice.
Methods: In AlCl3-induced AD model, four-month-old male Balb-c mice were subcutaneously injected with AlCl3 (50 mg/kg) daily for 8 consecutive weeks. At the same time, mice were intragastrically given IRN (20 and 40 mg/kg) or donepezil (5 mg/kg, positive control) 30 min before each AlCl3 injection. After drugs treatment, the spatial learning and memory functions were assessed with the radial arm maze (RAM) test. The anti-AD action mechanism of IRN was examined by measuring the parameters of oxidative stress, cholinergic system, apoptosis and nuclear factor kappa B (NF-ĸB) pathway in the brain tissues of AlCl3-treated mice. Male two-month-old TgCRND8 transgenic mice were randomly assigned to five groups of 10 animals each: (a) Wild-Type (WT); (b) Tg + vehicle; (c) and (d) Tg + IRN (20 mg/kg and 40 mg/kg, respectively); (e) Tg + donepezil (5 mg/kg) as positive control. Then, the mice were intragastrically given with IRN, donepezil or vehicle daily for 4 months, followed by assessing spatial learning and memory function with the RAM test. In mechanistic studies, the brain tissues were used to determine the effects of IRN on Aβ pathology, Aβ metabolism, APP processing and APP protein phosphorylation, and JNK pathway using the methods of western blotting, immunofluorescence and ELISA kits.
Results: The results demonstrated that both AlCl3-treated mice and TgCRND8 mice showed significant spatial learning and memory impairments in the RAM test. However, treatment with IRN could significantly ameliorate the cognitive deficits induced by AlCl3 and TgCRND8 transgenic mice. For mechanism studies, it was found that IRN treatment enhanced the activities of superoxide dismutases (SOD) and catalase (CAT) and the level of glutathione (GSH), but markedly inhibited the activity of acetylcholinesterase (AChE) and the level of malondialdehyde (MDA) in the brain tissues of AlCl3-treated mice. Moreover, IRN could significantly inhibit the phosphorylation of NF-ĸB p65 and IĸBα in the brain tissues of AlCl3-treated mice. However, IRN did not show significant effect on the activity of BuChE, the number of hippocampus neurons or the protein levels of Bcl-2/Bax. On the other hand, the results revealed that IRN treatment could notably alleviate the Aβ plaque, microgliosis and astrocytosis in the hippocampus of TgCRND8 mice. In addition, IRN treatment was able to obviously decrease the protein levels of Aβ1-40 and Aβ1-42 in the brain tissues of TgCRND8 mice. Moreover, IRN treatment could also significantly decreased the protein levels of BACE-1, PS-1, IDE, APH-1 and p-APP in the hippocampus of TgCRND8 mice.Importantly, IRN treatment could reduce the hyperphosphorylated of Tau at specific Thr205 site and the ratios of p-JNK/JNK and p-c-Jun/c-Jun in the brains of TgCRND8 mice.
Discussion and conclusion: Our findings indicated that IRN was able to improve the cognitive deficits induced by AlCl3 in mice via inhibiting the AChE activity and enhancing the antioxidant status of brain tissue through suppressing the NF-ĸB pathway. IRN could also ameliorate the learning and memory impairments in TgCRND8 transgenic mice via modulating the Aβ metabolism, altering the APP processing and phosphorylation, inhibiting tau protein phosphorylation and attenuating neuroinflammation through suppressing the activation of JNK signaling pathway.
All Author(s) List冼彥芳
Name of Conference寧夏醫科大學2019年國際醫學高峰論壇
Start Date of Conference15/10/2019
End Date of Conference18/10/2019
Place of Conference銀川
Country/Region of ConferenceChina
Year2019
Month10
LanguagesChinese-Simplified

Last updated on 2020-20-11 at 17:03