Abstract
Curculigoside (CUR) is the main active component of traditional Chinese medicine Curculigoorchioides Gaertn (Xianmao in Chinese), which exhibits a variety of pharmacological activities. In this study we investigated the effects of CUR on fear extinction and related depression-like behaviors in mice. In fear conditioning task, we found that administration of CUR (1.6, 8, 40 mg·kg−1·d−1, ip, for 7 days) did not affect memory consolidation, but CUR at higher doses (8, 40 mg·kg−1·d−1) significantly facilitated fear extinction, especially on D3 and D4. Moreover, CUR administration significantly ameliorated the fear conditioning-induced depression-like behaviors, likely through promoting fear extinction. We showed that CUR increased the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of tropomyosin receptor kinase B (TrkB) in the hippocampus, and activated protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) signaling pathway. Administration of the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF, 5 mg·kg−1·d−1, ip) also facilitated fear extinction, ameliorated depression-like behaviors. We established a mouse learned helplessness (LH) model to evaluate the antidepressant activity of CUR. The spatial memory was assessed in Morris water maze. We showed that LH-induced depression-like behaviors, including prolonged immobility times in forced swim and tail suspension tests as well as spatial memory impairments; LH also downregulated BDNF expression and the Akt-mTOR signaling pathway in the hippocampus. Administration of CUR (1.6, 8, 40 mg·kg−1·d−1, ip, for 14 days) or 7,8-DHF (5 mg·kg−1·d−1, ip, for 3 days) prevented LH-induced depression-like behaviors and promoted BDNF expression and the Akt-mTOR signaling pathway. In conclusion, CUR can accelerate the fear memory extinction and ameliorate depression-like behaviors in mice via promoting BDNF expression and activating the Akt-mTOR signaling pathway in the hippocampus.
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Acknowledgements
This research was supported by the National Natural Science Foundation of China (81601181, 81673716), the Anhui Natural Science Foundation (1808085J15) and the National Key R&D Program (2018YFC1204603).
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GQZ conceived, designed the experiments and wrote the manuscript; SJY, ZJS, XCW, ZRZ and SBW performed the experiments and analyzed the data.
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Yang, Sj., Song, Zj., Wang, Xc. et al. Curculigoside facilitates fear extinction and prevents depression-like behaviors in a mouse learned helplessness model through increasing hippocampal BDNF. Acta Pharmacol Sin 40, 1269–1278 (2019). https://doi.org/10.1038/s41401-019-0238-4
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DOI: https://doi.org/10.1038/s41401-019-0238-4
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