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Astragaloside IV shows neuroprotective activity, but its mechanism remains unclear. To investigate whether astragaloside IV protects from endoplasmic reticulum stress (ERS), we focus on the regulation of glycogen synthase kinase-3\u03b2 (GSK-3\u03b2) and mitochondrial permeability transition pore (mPTP) by astragaloside IV in neuronal cell PC12. Methods and Results. PC12 cells treated with different concentrations of ERS inductor 2-deoxyglucose (2-DG) (25-500\u2009\u03bcM) showed a significant increase of glucose-regulated protein 78 (GRP 78) and GRP 94 expressions and a decrease of tetramethylrhodamine ethyl ester (TMRE) fluorescence intensity and mitochondrial membrane potential (\u2206\u03a8m), with the peak effect seen at 50\u2009\u03bcM, indicating that 2-DG induces ERS and the mPTP opening. Similarly, 50\u2009\u03bcM of astragaloside IV increased the GSK-3\u03b2 phosphorylation at Ser9 most significantly. Next, we examined the neuroprotection of astragaloside IV by dividing the PC12 cells into control group, 2-DG treatment group, astragaloside IV plus 2-DG treatment group, and astragaloside IV only group. PC12 cells treated with 50\u2009\u03bcM 2-DG for different time courses (0-36\u2009hr) showed a significant increase of Cleaved-Caspase-3 with the peak at 6\u2009hr. 2-DG significantly induced cell apoptosis and increased the green fluorescence intensity of Annexin V-FITC, and these effects were reversed by astragaloside IV. Such a result indicates that astragaloside IV protected neural cell survival from ERS. 2-DG treatment significantly increased the expressions of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1), phosphor-protein kinase R-like ER kinase (p-PERK), but not affect the transcription factor 6 (ATF6) expression. 2-DG treatment significantly decreased the phosphorylation of GSK-3\u03b2 and significantly reduced the TMRE fluorescence intensity and \u2206\u03a8m, following mPTP open. Astragaloside IV significantly inhibited the above effects caused by 2-DG, except the upregulation of ATF6 protein. Taken together, astragaloside IV significantly inhibited the ERS caused by 2-DG. Conclusion. Our data suggested that astragaloside IV protects PC12 cells from ERS by inactivation of GSK-3\u03b2 and preventing the mPTP opening. The GRP 78, GRP 94, IRE1, and PERK signaling pathways but not ATF6 are responsible for GSK-3\u03b2 inactivation and neuroprotection by astragaloside IV.<\/jats:p>","DOI":"10.1155\/2020\/9782062","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T23:05:19Z","timestamp":1609455919000},"page":"1-11","source":"Crossref","is-referenced-by-count":16,"title":["Neuroprotection Effect of Astragaloside IV from 2-DG-Induced Endoplasmic Reticulum Stress"],"prefix":"10.1155","volume":"2020","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6009-4729","authenticated-orcid":true,"given":"Yu","family":"Fu","sequence":"first","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"},{"name":"Hebei Key Laboratory for Chronic Diseases, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-2010","authenticated-orcid":true,"given":"Jianhang","family":"Cai","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"},{"name":"Department of Neurology, Dongming People\u2019s Hospital, Dongming 274501, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4784-3796","authenticated-orcid":true,"given":"Mengyao","family":"Xi","sequence":"additional","affiliation":[{"name":"School of Nursing, Dalian Medical University, Dalian 116044, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9366-9907","authenticated-orcid":true,"given":"Yifei","family":"He","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-7640","authenticated-orcid":true,"given":"Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2193-9466","authenticated-orcid":true,"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7209-7452","authenticated-orcid":true,"given":"Yidong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5220-1192","authenticated-orcid":true,"given":"Jinkun","family":"Xi","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5293-0547","authenticated-orcid":true,"given":"Yonggui","family":"He","sequence":"additional","affiliation":[{"name":"Clinic School of Medicine and Affiliated Hospital, North China University of Science and Technology, Tangshan 063000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1016\/S0254-6272(13)60189-2"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.12232"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02360-5"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2019.1569697"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1186\/s40360-018-0241-2"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1080\/10715762.2017.1361532"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2017.12.019"},{"issue":"9","key":"8","doi-asserted-by":"crossref","DOI":"10.3390\/molecules24091838","article-title":"The role of astragaloside IV against cerebral ischemia\/reperfusion injury: suppression of apoptosis via promotion of P62-LC3-autophagy","volume":"24","author":"Y. 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