Isorhynchophylline Exerts Antidepressant-like Effects in Mice via Modulating Neuroinflammation and Neurotrophins: Involvement of PI3K/Akt/GSK-3β and NF-κB Signaling Pathways
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AbstractIsorhynchophylline (IRN), an oxindole alkaloid isolated from Uncaria rhynchophylla, elicited distinct anti-depressant-like activity in mice. The present study aimed to investigate the antidepressant-like effects of IRN in chronic unpredictable mild stress (CUMS) induced depressive-like behavior in mice, and to illustrate its possible mechanism(s) of action. The mice were subjected to CUMS for 6 weeks and administered with IRN (20 or 40 mg/kg) daily by oral gavage for 3 weeks. PI3K/Akt inhibitor and GSK-3β inhibitors were used to determine the involvement of PI3K/Akt/GSK-3β pathway in the antidepressant-like effects of IRN in mice. The results showed that CUMS caused depression-like behavior in mice, such as behavioral despair as detected by forced swim test and anhedonia by sucrose preference test. In addition, CUMS could significantly reduce the levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but markedly increase the release of TNF- α and IL-6 in the hippocampus and cerebral cortex of the mice. Western blotting analysis showed that CUMS could markedly suppress the levels of p-GSK-3β (Ser9) and p-Akt (Ser473), but significantly enhance the expressions of p-p65 in nucleus of the hippocampus and cerebral cortex of the mice. CUMS could also significantly increase the NF-κB binding activity in the hippocampus and cerebral cortex of the mice. IRN treatment could significantly reverse the behavioral and biochemical changes induced by CUMS in mice. Moreover, the anti-depressant-like effect of IRN could be completely abolished by PI3K/Akt inhibitor. Combination treatment with IRN and GSK-3β inhibitors in mice exerted a synergistic anti-immobility action in forced swim test. These results suggest that the antidepressant-like action of IRN may be mediated, at least in part, by enhancing neurotrophins and attenuating neuro-inflammation via modulating the PI3K/Akt/GSK-3β and NF-κB signaling pathway.
Acknowledgements
This work was supported by the Health and Medical Research Fund of Hong Kong (project 16170851) and The Chinese University of Hong Kong Direct Grant (project no. 2017.076).
All Author(s) ListYan-Fang Xian, Zhi-Xiu Lin, Chang Qu, Siu-Po Ip
Name of Conference3rd World Congress on Pharmacology and Clinical Trials
Start Date of Conference19/08/2019
End Date of Conference20/08/2019
Place of ConferenceKuala Lumpur
Country/Region of ConferenceMalaysia
Proceedings Title3rd World Congress on Pharmacology and Clinical Trials Scientific Program
Year2019
Month8
LanguagesEnglish-United Kingdom

Last updated on 2020-20-11 at 12:46