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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Calpain-1 deletion elicits neurodevelopmental disorders, such as ataxia. However, the function of calpain in postnatal neurodevelopment and its mechanisms remain unknown. In this study, we revealed that postnatal intraperitoneal injection of various calpain inhibitors attenuated cerebellar cytosolic calpain activity. Moreover, postnatal application of calpeptin (2 mg/kg) apparently reduced spectrin breakdown, promoted suprachiasmatic nucleus circadian oscillatory protein (SCOP) accumulation in cerebellar tissue. In addition, application of calpeptin decreased phosphorylated protein kinase B (p-AKT) level (p<0.05), as well as total AKT level (p<0.05). We also evidenced that administration of calpeptin obviously increased phosphorylation of mammalian target of rapamycin (p-mTor) (p<0.01). Apoptosis of granular cells and activation of caspase-3 (p<0.01) were facilitated after calpain inhibition. Importantly, cell numbers of granular cells were reduced and motor function was remarkably impaired in 4-month-old rats receiving postnatal calpain inhibition. Taken together, our data implicated that calpain activity in the postnatal period was critical for the cerebellar development. Postnatal calpain inhibition causes cerebellar granular cell apoptosis and motor dysfunction, likely through SCOP/AKT and p-mTor signaling pathways.

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