Notoginsenoside R1 Protects against Neonatal Cerebral Hypoxic-Ischemic Injury through Estrogen Receptor-Dependent Activation of Endoplasmic Reticulum Stress Pathways

作者：Wang, Yan; Tu, Liu; Li, Yingbo; Chen, Di; Wang, Shali^*

来源：Journal of Pharmacology and Experimental Therapeutics, 2016, 357(3): 591-605.

DOI：10.1124/jpet.115.230359

• ER STRESS
• REPERFUSION INJURY
• CELL-DEATH
• IN-VITRO
• APOPTOSIS
• BRAIN
• MECHANISMS
• INDUCTION
• ISCHEMIA/REPERFUSION
• INVOLVEMENT

Notoginsenoside R1 (NGR1) is a phytoestrogen that is isolated from Panax notoginseng. It is used in China to treat many diseases, including hypoxic-ischemic encephalopathy (HIE), 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 mechanisms of NGR1 in neonatal HIE is unclear. In this study, oxygenglucose deprivation/reoxygenation (OGD/R) in primary cortical neurons and unilateral ligation of the common carotid artery (CCL), followed by exposure to a hypoxic environment in 7-day-old postnatal Sprague-Dawley rats were used to mimic HIE episodes. Potential neuroprotective effects of NGR1 against neonatal HIE and its mechanisms were examined. After HIE conditions in vitro and in vivo, we administered NGR1 or the estrogen receptor inhibitor ICI-182780 and measured cell apoptosis, brain injury by MTT assay, TTC stain, and so forth. Expression of estrogen receptors alpha (ER alpha) and beta (ER beta), ER stress-associated proteins was detected by Western blot upon stimulation with HIE, NGR1, or ICI-182780. Results showed that after HIE, ER chaperone GRP78 was activated, ER stress-associated proapoptotic proteins (CHOP, PERK, ERO1-alpha, and IRE1 alpha) were increased, caspase-12 was increased, and BCL-2 was decreased. The ER stress response and neuronal apoptosis were attenuated by NGR1 treatment. However, neuroprotective properties of NGR1 against HIE-induced apoptosis and ER stress were attenuated by ICI-182780. These results suggest that NGR1 may be an effective treatment of HIE by reducing ER stress-induced neuronal apoptosis and brain injury via estrogen receptors.

• 出版日期2016-6
• 单位重庆医科大学