Abstract
Notoginsenoside R1 (NGR1) is a phytoestrogen, which can be isolated from Panax notoginseng. It is used to treat many diseases including hypoxic-ischemic injury, and it has been shown to target estrogen receptors. Endoplasmic reticulum (ER) stress plays an important role in the development of cell apoptosis during ischemia, and ER stress is known to be regulated by estrogen. However, the neuroprotective properties and underlying mechanisms of NGR1 in neonatal hypoxic-ischemic encephalopathy (HIE) and the relationship between NGR1 and ER stress is unknown. This study examined potential neuroprotective effects of NGR1 against neonatal HIE and its mechanisms. Following HIE conditions in vitro and in vivo, we administered NGR1 or the estrogen receptor inhibitor ICI-182780 and then measured cell apoptosis and brain injury. Expression of estrogen receptors α (ERα) and β (ERβ), and ER stress-associated proteins was detected by western blot upon stimulation with HIE, NGR1, or ICI-182780. Results showed that hypoxia-ischemia clearly induced neuronal apoptosis and brain injury. Following hypoxia-ischemia, ER chaperon GRP78 was activated, and the ER stress-associated pro-apoptotic proteins (CHOP, PERK, ERO1-α, and IRE1α) were increased. Expression of caspase-12 increased and expression of BCL-2 decreased under stress conditions both in vitro and in vivo. The ER stress response and neuronal apoptosis were attenuated by NGR1 treatment. However, the neuroprotective properties of NGR1 against hypoxia-ischemia-induced apoptosis and ER stress were attenuated by ICI-182780. These results suggest that NGR1 may be an effective treatment for HIE by reducing ER stress-induced neuronal apoptosis and brain injury via estrogen receptors.
- The American Society for Pharmacology and Experimental Therapeutics