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Protective effect of mesenchymal stem cell-derived exosomal treatment of hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury

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World Journal of Emergency Medicine 2022年第1期13卷 46-53页

作者： Xiao-fang Guo Shuang-shuang Gu Jun Wang Hao Sun Yu-juan Zhang Peng-fei Yu Jin-song Zhang Lei Jiang Department of Emergency the First Affi liated Hospital of Nanjing Medical UniversityNanjing 210029China Key Laboratory of Modern Toxicology Ministry of EducationDepartment of ToxicologySchool of Public HealthNanjing Medical UniversityNanjing 211166China Key Laboratory of Modern Toxicology Ministry of EducationDepartment of Environmental GenomicsSchool of Public HealthNanjing Medical UniversityNanjing 211166China Center for Drug Safety Evaluation and Research Shanghai Institute of Materia MedicaShanghai 201203China

BACKGROUND:Individuals who survive a cardiac arrest often sustain cognitive impairments due to ischemia-reperfusion injury.Mesenchymal stem cell(MSC)transplantation is used to reduce tissue damage,but exosomes are more stable and highly conserved than MSCs.This study was conducted to investigate the therapeutic effects of MSC-derived exosomes(MSC-Exo)on cerebral ischemia-reperfusion injury in an in vitro model of oxygen-glucose deprivation/reperfusion(OGD/R),and to explore the underlying mechanisms.METHODS:Primary hippocampal neurons obtained from 18-day Sprague-Dawley rat embryos were subjected to OGD/R treatment,with or without MSC-Exo treatment.Exosomal integration,cell viability,mitochondrial membrane potential,and generation of reactive oxygen species(ROS)were examined.Terminal deoxynucleotidyl transferase-mediated 2’-deoxyuridine 5’-triphosphate nickend labeling(TUNEL)staining was performed to detect neuronal apoptosis.Moreover,mitochondrial function-associated gene expression,Nrf2 translocation,and expression of downstream antioxidant proteins were determined.RESULTS:MSC-Exo attenuated OGD/R-induced neuronal apoptosis and decreased ROS generation(P<0.05).The exosomes reduced OGD/R-induced Nrf2 translocation into the nucleus(2.14±0.65 vs.5.48±1.09,P<0.01)and increased the intracellular expression of antioxidative proteins,including superoxide dismutase and glutathione peroxidase(17.18±0.97 vs.14.40±0.62,and 20.65±2.23 vs.16.44±2.05,respectively;P<0.05 for both).OGD/R significantly impaired the mitochondrial membrane potential and modulated the expression of mitochondrial functionassociated genes,such as PINK,DJ1,LRRK2,Mfn-1,Mfn-2,and OPA1.The abovementioned changes were partially reversed by exosomal treatment of the hippocampal neurons.CONCLUSIONS:MSC-Exo treatment can alleviate OGD/R-induced oxidative stress and dysregulation of mitochondrial function-associated genes in hippocampal neurons.Therefore,MSCExo might be a potential therapeutic strategy to prevent OGD/R-induced neuronal injury.

关键词： Mesenchymal stem cells Exosomes oxygen-glucose deprivation/reperfusion Reactive oxygen species Mitochondria

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Intervention Timing and Effect of PJ34 on Astrocytes During oxygen-glucose deprivation/reperfusion and Cell Death Pathways

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2015年第3期35卷 397-404页

作者：蔡川张睿黄巧英曹旭邹良玉褚晓凡 Department of Neurology Second Clinical College Jinan University Research Centre for Neural Engineering Institute of Biomedical and Health Engineering Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences

Poly （ADP-ribose） polymerase-I （PARP-1） plays as a double edged sword in cerebral ischemia-reperfusion, hinging on its effect on the intracellular energy storage and injury severity, and the prognosis has relationship with intervention timing. During ischemia injury, apoptosis and oncosis are the two main cell death pathway sin the ischemic core. The participation of astrocytes in ische- mia-reperfusion induced cell death has triggered more and more attention. Here, we examined the pro- tective effects and intervention timing of the PARP-1 inhibitor PJ34, by using a mixed oxygen-glucose deprivation/reperfusion （OGDR） model of primary rat astrocytes in vitro, which could mimic the ische- mia-reperfusion damage in the ＂ischemic core＂. Meanwhile, cell death pathways of various P J34 treated astrocytes were also investigated. Our results showed that P J34 incubation （10 μmol/L） did not affect release of lactate dehydrogenase （LDH） from astrocytes and cell viability or survival 1 h after OGDR. Interestingly, after 3 or 5 h OGDR, P J34 significantly reduced LDH release and percentage of PI-positive cells and increased cell viability, and simultaneously increased the caspase-dependent apop- totic rate. The intervention timing study demonstrated that an earlier and longer P J34 intervention dur- ing reperfusion was associated with more apparent protective effects. In conclusion, earlier and longer PJ34 intervention provides remarkable protective effects for astrocytes in the ＂ischaemic core＂ mainly by reducing oncosis of the astrocytes, especially following serious OGDR damage.

关键词： PARP-1 inhibitor PJ34 primarycortical astrocyte oxygen-glucose deprivation/reperfusion oncosis apoptosis

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Blockade of HCN2 Channels Provides Neuroprotection Against Ischemic Injury via Accelerating Autophagic Degradation in Hippocampal Neurons

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Neuroscience Bulletin 2020年第8期36卷 875-894页

作者： Cheng Chen Li Liu Ya-Qiao Shu Ping Jing Yun Lu Xiao-Xue Zhang Xian-Gang Zong Lian-Jun Guo Chang-Jun Li Department of Pharmacology School of Basic Medical SciencesTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Neurology The Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Office of Academic Research The Central Hospital of WuhanTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Pharmacy Zhongnan Hospital of Wuhan UniversityWuhan 430030China Department of Clinical Laboratory Wuhan PuAi HospitalWuhan 430033China Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation Wuhan 430030China Center for Integrated Protein Science and Zentrum fur Pharmaforschung Department PharmazieLudwig-Maximilians-Universitat Miinchen80539 MunichGermany

In the central nervous system,hyperpolarizationactivated cyclic nucleotide-gated(HCN)channels are essential to maintain normal neuronal function.Recent studies have shown that HCN channels may be involved in the pathological process of ischemic brain injury,but the mechanisms remain unclear.Autophagy is activated in cerebral ischemia,but its role in cell death/survival remains controversial.In this study,our results showed that the HCN channel blocker ZD7288 remarkably decreased the percentage of apoptotic neurons and corrected the excessive autophagy induced by oxygen-glucose deprivation followed by reperfusion(OGD/R)in hippocampal HT22 neurons.Furthermore,in the OGD/R group,p-mTOR,p-ULK1(Ser757),and p62 were significantly decreased,while p-ULK1(Ser317),atg5,and beclin1 were remarkably increased.ZD7288 did not change the expression of p-ULK1(Ser757),ULK1(Ser317),p62,Beclin1,and atg5,which are involved in regulating autophagosome formation.Besides,we found that OGD/R induced a significant increase in Cathepsin D expression,but not LAMP-1.Treatment with ZD7288 at 10μmol/L in the OGD/R group did not change the expression of cathepsin D and LAMP-1.However,chloroquine(CQ),which decreases autophagosome-lysosome fusion,eliminated the correction of excessive autophagy and neuroprotection by ZD7288.Besides,shRNA knockdown of HCN2 channels significantly reduced the accumulation of LC3-Ⅱand increased neuron survival in the OGD/R and transient global cerebral ischemia(TGCI)models,and CQ also eliminated the effects of HCN2-shRNA.Furthermore,we found that the percentage of LC3-positive puncta that co-localized with LAMP-1-positive lysosomes decreased in Con-shRNAtransfected HT22 neurons exposed to OGD/R or CQ.In HCN2-shRNA-transfected HT22 neurons,the percentage of LC3-positive puncta that co-localized with LAMP-1-positive lysosomes increased under OGD/R;however,the percentage was significantly decreased by the addition of CQ to HCN2-shRNA-transfected HT22 neurons.The present results demonstrated that blockade of HCN2 channel

关键词： HCN2 channel Autophagy Neuroprotection oxygen-glucose deprivation/reperfusion Transient global cerebral ischemia

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Inhibition of caspases and intracellular free Ca2+ concentrations are involved in resveratrol protection against apoptosis in rat primary neuron cultures

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Acta Pharmacologica Sinica 2007年第11期28卷 1724-1730页

作者： Qi-hai GONG~(2,3,4),Qian WANG~(2,3),Jing-shan SHI~(2,3),Xie-nan HUANG~(2,3),Qiong LIU~2,Hu MA~2~2 Department of Pharmacology,Zunyi Medical College,Zunyi 563000,China ~3 the Key Laboratory of Basic Pharmacology of GuizhouProvince,Zunyi Medical College,Zunyi 563000,China Department of Pharmacology Zunyi Medical College Zunyi China Key Laboratory of Basic Pharmacology of Guizhou Province Zunyi Medical College Zunyi China

Aim:To investigate the influence of resveratrol （Res）,a nutritional antioxidant,onthe inhibition of apoptosis in rat primary neuron cultures.Methods:The culturedcortical neurons of neonatal Sprague-Dawley rats were pretreated with Res （0.1,1.0,and 10.0 μmol/L） and oxygen-glucose deprivation/reperfusion （OGD/RP） withoxygen and glucose were initiated at d 10 in vitro.Neuronal apoptosis wasdetermined by flow cytometry,and morphological changes of neurons wereobserved by an electron microscope.For the mechanism studies,the intracellularfree calcium concentration ([Ca2+]i) and the transcription of caspases-3 and-12 inneurons were detected by Fura 2/AM loading and real-time RT-PCR,respectively.Results:OGD/RP insult could induce an increase in the apoptotic rate of neurons（from 11.1% to 49.0%）,and elicit an obvious morphological change in neurons;pretreatments with Res （0.1,1.0,and 10.0 μmol/L,respectively） significantlyreduced the elevated rate of apoptosis to 41.7%,40.8%,and 37.4%,respectively,and ameliorated the neuronal morphological injury.Similarly,the OGD/RP insultobviously elicited the elevated levels of the [Ca2+]iand the expressions of caspases-3and-12 mRNA in neurons.Res pretreatments markedly depressed the neuronalabnormal elevation of [Ca2+]iand the overexpression of caspases-3 and-12 mRNAin a concentration-dependent manner.Conclusion:Res can attenuate the ratcortical neuronal apoptosis induced by OGD/RP.The mechanisms are,at leastpartly,due to the inhibition of the calcium overload and the overexpression ofcaspases-3 and-12 mRNA.

关键词： resveratrol oxygen-glucose deprivation/reperfusion brain ischemia apoptosis neurons

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