Isorhynchophylline Improves Learning and Memory Impairments on TgCRND8 Transgenic Mice
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AbstractBackground and Aims: 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, 異鉤藤堿 ) is a c-22 oxindole alkaloid 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. TgCRND8 transgenic (Tg) mice express a transgene incorporating both the Indiana mutation (V717F) and the Swedish mutation (K670N/M671L) in the human amyloid-β protein precursor (APP) gene. To provide more scientific rationale and justification for future clinical study on this antiAD alkaloid, the present project aimed to investigate the cognitive deficit ameliorating effects of IRN on TgCRND8 transgenic mice.
Methods: The mice were bred and maintained in RRSSB. The genotyping of mice were carried out with the primer: F-TGTCCAAGATGCAGCAGAACGGCTAC, R-GGCCGCGGAGAAATGAAGAAACGCCA. At the age of two months, the 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. The mice were orally given daily with IRN, donepezil or vehicle and lasted for 4 months, followed by assessing spatial learning and memory function by the Radial Arm Maze (RAM) test. In the RAM test, three behavioural measurements were recorded: (1) number of total entries to complete the test, (2) number of reference memory errors (RMEs), i.e. entries into a non-baited arm, (3) number of working memory errors (WMEs), i.e. re-entries into an already visited baited arm. Twenty-four hours after the RAM test, mice were sacrificed and the brain tissues were harvested for mechanistic studies. The mechanism underlying the antiAD action of IRN was examined by measuring the parameters of APP processing and phosphorylation, tau protein phosphorylation and neuroinflammation in the brain tissues.
Results: The results showed that TgCRND8 mice express significant spatial learning and memory impairments in the RAM test when compared with the WT mice. IRN (40 mg/kg) treatment significantly decreased the number of total entries to complete the maze by 31.91% (p < 0.05), RMEs by 28.89% (p < 0.05) and WMEs by 51.30% (p < 0.05) as compared with the Tg + vehicle group. In the mechanistic studies, IRN (40 mg/kg) treatment significantly decreased the levels of BACE-1 by 49.41% (p < 0.05) PS-1 by 43.58% (p < 0.05), APH-1 by 50.43% (p < 0.05) and p-APP by 62.31% (p < 0.01). IRN (40 mg/kg) also reduced the ratios of p-JNK/JNK and p-c-Jun/c-Jun by 38.08% (p < 0.01) and 39.52% (p < 0.05), respectively. Moreover, IRN (40 mg/kg) reduced the hyperphosphorylated Tau at specific Thr205 site by 54.41% (p < 0.01) in the brains of TgCRND8 mice when compared with the Tg + vehicle group. The levels of Aβ plaque, Iba-1 and GFAP were also decreased after treatment with IRN (20 and 40 mg/kg).
Conclusions: Our findings indicated that IRN had therapeutic effects on TgCRND8 transgenic mice. The protective effect of IRN against TgCRND8 transgenic mice is probably mediated through altering the APP processing and phosphorylation, inhibiting tau protein phosphorylation, decreasing Aβ plaque and alleviating neuroinflammation via suppressing the activation of JNK signaling pathway.
All Author(s) ListHui-Qin LI, Yan-Fang XIAN, Zhixiu LIN
Name of ConferenceInternational Conference on Brain Research in Chinese Medicine: Degeneration and Repair
Start Date of Conference26/07/2018
End Date of Conference28/07/2018
Place of ConferenceHong Kong
Country/Region of ConferenceHong Kong
Proceedings TitleInternational Conference on Brain Research in Chinese Medicine: Degeneration and Repair
Year2018
Month7
LanguagesEnglish-United Kingdom

Last updated on 2019-24-10 at 12:55