Abstract
As documented in our previous study, notoginsenoside R1 (NGR1) can inhibit neuron apoptosis and the expression of endoplasmic reticulum (ER) stress-associated pro-apoptotic proteins in hypoxic–ischemic encephalopathy. Recent evidence indicates that the Phospholipase C (PLC)/inositol 1,4,5-trisphosphate receptor (IP3R) is important for the regulation of Ca2+ release in the ER. Ca2+ imbalance can stimulate ER stress, CAMKII, and cell apoptosis. The purpose of this study was to further investigate the neuroprotective effect of NGR1 and elucidate how NGR1 regulates ER stress and cell apoptosis in the oxygen–glucose deprivation/reoxygenation (OGD/R) model. Cells were exposed to NGR1 or the PLC activator m-3M3FBS. Then, IP3R- and IP3-induced Ca2+ release (IICR) and activation of the ER stress and CaMKII signal pathway were measured. The results showed that NGR1 inhibited IICR and strengthened the binding of GRP78 with PERK and IRE1. NGR1 also alleviated the activation of the CaMKII pathway. Pretreatment with m-3M3FBS attenuated the neuroprotective effect of NGR1; IICR was activated, activation of the ER stress and CaMKII pathway was increased, and more cells were injured. These results indicate that NGR1 may suppress activation of the PLC/IP3R pathway, subsequently inhibiting ER Ca2+ release, ER stress, and CaMKII and resulting in suppressed cell apoptosis.
Highlights
It is well known that the loss of Ca2+ homeostasis plays an important role in ischemia-induced neuronal damage[10,11] upon oxygen–glucose deprivation/reoxygenation (OGD/R), a well-established in vitro model of ischemia[12]
OGD/R treatment increased the expression of p-PLCβ and p-PLCγ compared to the control group, but notoginsenoside R1 (NGR1) decreased the phosphorylation of PLCβ and PLCγ (Fig. 1)
To detect whether NGR1 could strengthen the cooperation between GRP78 and PERK/IRE1 via Phospholipase C (PLC), cells were exposed to m-3M3FBS 1 h before OGD/R
Summary
It is well known that the loss of Ca2+ homeostasis plays an important role in ischemia-induced neuronal damage[10,11] upon oxygen–glucose deprivation/reoxygenation (OGD/R), a well-established in vitro model of ischemia[12] In this model, substantial Ca2+ is released from the ER, resulting in an increased Ca2+ concentration in the cytosol[13]. The above findings suggest that inhibiting the activation PLC/IP3R may be effective for regulating the ER Ca2+–ER stress and ER Ca2+–CaMKII signal pathway and cell apoptosis. To the best of our knowledge, this study was the first to show that the neuroprotective effects of NGR1 against OGD/R may suppress the activation of the PLC pathway to regulate the ER stress and CaMKII signal pathway
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