Abstract
Hormesis is an adaptive response of living organisms to a moderate stress. However, its biomedical implication and molecular mechanisms remain to be intensively investigated. Panaxatriol saponins (PTS) is the major bioactive components extracted from Panax notoginseng, a widely used herbal medicine for cerebrovascular diseases. This study aims to examine the hormetic and neuroprotective effects of PTS in PC12 cells and zebrafish Parkinson’s disease (PD) models. Our results demonstrated that PTS stimulated PC12 cell growth by about 30% at low doses, while PTS at high doses inhibited cell growth, which is a typical hormetic effect. Moreover, we found that low dose PTS pretreatment significantly attenuated 6-OHDA-induced cytotoxicity and up-regulated PI3K/AKT/mTOR cell proliferation pathway and AMPK/SIRT1/FOXO3 cell survival pathway in PC12 cells. These results strongly suggested that neuroprotective effects of PTS may be attributable to the hormetic effect induced by PTS through activating adaptive response-related signaling pathways. Notably, low dose PTS could significantly prevent the 6-OHDA-induced dopaminergic neuron loss and improve the behavior movement deficiency in zebrafish, whereas relative high dose PTS exhibited neural toxicity, further supporting the hormetic and neuroprotective effects of PTS. This study indicates that PTS may have the potential in the development of future therapeutic medicines for PD.
Highlights
Hormesis refers to a process in which exposure to a low dose of an environmental factor that is damaging at higher doses induces an adaptive beneficial effect on the cell or organism[1]
We firstly demonstrated that the neuroprotective activity of Panaxatriol saponins (PTS) in 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) models in PC12 cells and zebrafish was attributable to PTS-elicited hormetic effect via regulating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin and AMP-activated protein kinase (AMPK)/sirtuin-1 (SIRT1)/Forkhead box O3 (FOXO3) pathways
Inhibition of AMPK by CC significantly reversed the increased SIRT1 expression level (Fig. 3B). These results indicated that the hormetic effect of PTS at low doses on PC12 cells were through activating PTEN/PI3K/AKT/ mammalian target of rapamycin (mTOR) and AMPK/SIRT1/FOXO3 signaling pathways
Summary
Hormesis refers to a process in which exposure to a low dose of an environmental factor (physical, chemical or biological) that is damaging at higher doses induces an adaptive beneficial effect on the cell or organism[1]. A broad range of chemical agents, such as neurotrophic factors, antiexcitotoxins, steroids and phytochemicals that have been found to promote neuronal survival and neurite outgrowth, generally exhibit biphasic hormetic dose-responses[12]. A highly valued medicinal herb, is efficacious in the prevention and treatment of cardioand cerebro-vascular diseases and wound healing[13]. It can significantly improve animal’s learning and memory, reduce neural cell apoptosis and infarct size after cerebral ischemia[14]. We firstly demonstrated that the neuroprotective activity of PTS in 6-hydroxydopamine (6-OHDA)-induced PD models in PC12 cells and zebrafish was attributable to PTS-elicited hormetic effect via regulating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)/sirtuin-1 (SIRT1)/Forkhead box O3 (FOXO3) pathways
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