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Ginkgolide B‑Induced AMPK Pathway Activation Protects Astrocytes by Regulating Endoplasmic Reticulum Stress, Oxidative Stress

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Ginkgolide B‑Induced AMPK Pathway Activation Protects Astrocytes by Regulating Endoplasmic Reticulum Stress, Oxidative Stress MOLECULAR MEDICINE REPORTS 23: 457, 2021 Ginkgolide B‑induced AMPK pathway activation protects astrocytes by regulating endoplasmic reticulum stress, oxidative stress and energy metabolism induced by Aβ1‑42 JING WANG1‑4, YAN DING1,2, LINWU ZHUANG1,2, ZHENZHONG WANG3,4, WEI XIAO3,4 and JINGBO ZHU1,2 1School of Food Science and Technology and 2Institute of Chemistry and Applications of Plant Resources, Dalian Polytechnic University, Dalian, Liaoning 116034; 3Jiangsu Kanion Pharmaceutical Co. Ltd.; 4State Key Laboratory of Pharmaceutical New‑tech for Chinese Medicine, Lianyungang, Jiangsu 222000, P.R. China Received July 20, 2020; Accepted January 11, 2021 DOI: 10.3892/mmr.2021.12096 Abstract. Ginkgolide B (GB), the diterpenoid lactone levels of MDA and ROS in astrocytes, while compound C compound isolated from the extracts of Ginkgo biloba leaves, reversed the anti‑oxidative effect and the involvement of GB significantly improves cognitive impairment, but its potential in maintaining energy metabolism in astrocytes. Finally, GB pharmacological effect on astrocytes induced by β‑amyloid decreased the expression levels of the endoplasmic reticulum (Aβ)1‑42 remains to be elucidated. The present study aimed to stress (ERS) proteins and the apoptotic protein CHOP and investigate the protective effect and mechanism of GB on astro‑ increased both mRNA and protein expression of the compo‑ cytes with Aβ1‑42‑induced apoptosis in Alzheimer's disease nents of the energy metabolism‑related AMPK/peroxisome (AD). Astrocytes obtained from Sprague Dawley rats were proliferator‑activated receptor γ coactivator 1α/peroxisome randomly divided into control, Aβ, GB and GB + compound C proliferator‑activated receptor α and anti‑oxidation‑related groups. Cell viability and apoptosis were analyzed using nuclear respiratory factor 2/heme oxygenase 1/NAD(P)H Cell Counting Kit‑8 and flow cytometry assays, respectively. dehydrogenase (quinone 1) pathways and downregulated the Protein and mRNA expression levels were analyzed using expression of β‑secretase 1. However, compound C could western blotting and reverse transcription‑quantitative PCR, antagonize these effects. In conclusion, the findings demon‑ respectively. The levels of superoxide dismutase (SOD), strated that GB protected against Aβ1‑42‑induced apoptosis by malondialdehyde (MDA), glutathione peroxidase (GSH‑Px), inhibiting ERS, oxidative stress, energy metabolism disorders reactive oxygen species (ROS) and ATP were determined and Aβ1‑42 production probably by activating AMPK signaling using the corresponding commercial kits. The findings pathways. The findings provided an innovative insight into the revealed that GB attenuated Aβ1‑42‑induced apoptosis and treatment using GB as a therapeutic in Aβ1‑42‑related AD. the 5' adenosine monophosphate‑ activated protein kinase (AMPK) inhibitor compound C reversed the protective effects Introduction of GB. In addition, GB reversed Aβ1‑42‑induced oxidative damage and energy metabolism disorders, including decreases Ginkgolide B (GB) is one of the main components of the in the levels of SOD, GSH‑Px and ATP and increased the extracts of Ginkgo biloba leaves and the pharmacodynamic component with the strongest activity and the highest speci‑ ficity of the Ginkgo diterpenoid lactones (1). GB has been found to possess notable effects on the central nervous system, such as improving the cognitive function of patients with Correspondence to: Professor Wei Xiao, Jiangsu Kanion Alzheimer's disease (AD) and promoting the neuroprotective Pharmaceutical Co. Ltd., 58 Kangyuan Road, Lianyungang, Jiangsu 222000, P.R. China effects on acute hypoxic/ischemic injury (2,3). The high purity E‑mail: [email protected] of GB enables it to pass through the blood‑brain barrier and be easily absorbed, which is beneficial in the treatment of neurode‑ Professor Jingbo Zhu, School of Food Science and Technology, Dalian generative diseases (4,5), including AD, which is a destructive Polytechnic University, 1 Chigong Yuan, Dalian, Liaoning 116034, central nervous system lesion characterized by declining P.R. China E‑mail: [email protected] learning, memory loss and cognitive dysfunction (6,7). At present, the pathogenesis of AD remains to be elucidated, but Key words: ginkgolide B, astrocytes, β‑amyloid1‑42, endoplasmic it is well known that the abnormal metabolism and deposition reticulum stress, oxidative stress, energy metabolism disorder, of β‑amyloid (Aβ) in the brain tissues contribute to AD (8). 5' adenosine monophosphate‑activated protein kinase, Alzheimer's Activated astrocytes are found around Aβ deposition (9,10) disease and are the most abundant type of cells in the central nervous system. A previous study indicates that astrocytes induce Aβ degradation and clearance and the degradation of Aβ mediated 2 WANG et al: GINKGOLIDE B‑INDUCED AMPK PROTECTS ASTROCYTES by astrocytes is impeded in the early stage of AD (11). Thus, (cat. no. P0012S) and BSA (cat. no. ST023) were purchased astrocytes have regulatory roles in the onset of AD (12). GB from Beyotime Institute of Biotechnology. Minibest universal has been found to have clinical effects on neuroprotection (13), RNA extraction kit (cat. no. 9767), PrimeScript™ RT reagent but the protective effect of GB on astrocytes in AD and its kit with gDNA eraser (perfect real time; cat. no. RR047) potential molecular mechanism remain to be elucidated. and TB Green® Premix Ex Taq™ (Tli RNase H Plus; Aβ is the main factor leading to AD cognitive dysfunction cat. no. RR420) were purchased from Takara Bio Inc. and neurodegeneration because the excessive generation and DMEM/F12 medium (cat. no. C11330500BT) and fetal aggregation of Aβ results in a series of pathological and physi‑ bovine serum (cat. no. 10099141C) were purchased from ological changes, including endoplasmic reticulum (ER) stress Gibco (Thermo Fisher Scientific, Inc.). Clarity Western ECL (ERS), oxidative stress (OS), inflammatory response, energy substrate was purchased from Bio‑Rad Laboratories, Inc. metabolism disorder, tau hyperphosphorylation, synaptic Compound C, antibodies against β‑actin (cat. no. 4970; rabbit; degeneration, cell dysfunction and even apoptosis, causing 1:1,000), β‑secretase (BACE1; cat. no. 5606; rabbit; 1:1,000), abnormal learning, memory, cognition and behavior (14,15). β‑tubulin (cat. no. 6181; rabbit; 1:1,000), protein kinase The aforementioned pathological processes interact with each RNA‑like endoplasmic reticulum kinase (PERK; Phospho other, stimulating the onset and progression of AD. Thr980; cat. no. 3179; rabbit; 1:1,000), PERK (cat. no. 3192; ER, which takes part in protein synthesis, post‑translational rabbit; 1:1,000), eukaryotic translation initiation factor 2 modification and correct folding of proteins, is necessary to subunit α (eIF2α; PhosphoSer51; cat. no. 5199; rabbit; 1:1,000), maintain the normal function of cells (16). ER dysfunction or eIF2α (cat. no. 9079; rabbit; 1:1,000), 5' adenosine monophos‑ loss of integrity causes ERS, which is key to neurodegenerative phate‑activated protein kinase (AMPK; Phospho Thr172; diseases (17,18). Previous studies on patients with AD and the cat. no. 2531; rabbit; 1:1,000), AMPK (cat. no. 2532; rabbit; brain tissues of animal models demonstrate that Aβ seriously 1:1,000), heme oxygenase 1 (HO‑1; cat. no. 82206; rabbit; disturbs the functions of ER, leading to excessive generation 1:1,000) were purchased from Cell Signaling Technology, Inc., of Aβ, ERS activation (19,20) and finally cell dysfunction and inositol‑requiring enzyme 1 α (IRE1α; cat. no. 37073; rabbit; apoptosis (21). A previous study showed that mitochondrial 1:1,000), proliferator‑activated receptor γ coactivator 1 α damage was important in the pathogenesis of AD because mito‑ (PGC‑1α; cat. no. 54481; rabbit; 1:1,000), C/EBP‑homologous chondria supplied energy, exchanged information, antagonized protein (CHOP; cat. no. 179823; rabbit; 1:1,000), 78 kDa OS and provided energy for various cellular activities (22). The glucose‑regulated protein (GRP78; cat. no. 108613; overaggregation of Aβ influences the energy metabolism of rabbit; 1:1,000), activating transcription factor 6 (ATF6; mitochondria, decreases the generation of ATP and produces cat. no. 203119; rabbit; 1:1,000), nuclear factor erythroid numerous oxygen radicals in the mitochondria to weaken 2‑related factor 2 (Nrf2; cat. no. 137550; rabbit; 1:1,000), the ability of cells to provoke oxidation and cause OS (23), NAD(P)H dehydrogenase (quinone 1) (NQO1; cat. no. 28947; resulting in apoptosis (24). Meanwhile, oxides and lipid rabbit; 1:1,000) and peroxisome proliferator‑activated receptor peroxides increase the levels of the key amylase β secretase 1 α (PPARα; cat. no. 215270; rabbit; 1:1,000) were obtained from (BACE1) to cause the excessive generation of Aβ (25). The two Abcam. All primers were purchased from Sangon Biotech interact with each other to cause malignancy, mitochondrial Co., Ltd. dysfunction and serious oxidative injury, thus exacerbating the toxic responses of Aβ (26). Astrocytes are important in neuro‑ Animals. A total of 3 pregnant Sprague Dawley (SD) rats degenerative diseases and preventing the abnormal changes in (age, 2 months; 2‑3 weeks pregnancy; weight, 260‑270 g) astrocytes may help treat the diseases (27,28). Therefore, the were purchased from Experimental Animal Center, Yangzhou following hypothesis was proposed in the present study: GB University (Yangzhou, China). The rats were accommodated might antagonize the neurotoxicity of Aβ, prevent
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