title: Notoginsenoside R1 Protects against Neonatal Cerebral Hypoxic-Ischemic Injury through Estrogen Receptor-Dependent Activation of Endoplasmic Reticulum Stress Pathways.
abstract: 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, oxygen-glucose 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 α (ERα) and β (ERβ), 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-α, and IRE1α) 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.
authors.affiliation: Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Tu
authors.affiliation: Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China 63557408@qq.com.
authors.forename: Shali
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D036145:Ginsenosides / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D036145:Ginsenosides; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C072936:notoginsenoside R1