ASN NEURO最新文献_第10页

Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination Gas6促进成人中枢神经系统少突胶质形成和髓鞘形成，以及溶索磷脂诱导的脱髓鞘形成

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-09-01 DOI: 10.1177/1759091416668430

S. Goudarzi, Andrea D Rivera, A. Butt, S. Hafizi

{"title":"Gas6 Promotes Oligodendrogenesis and Myelination in the Adult Central Nervous System and After Lysolecithin-Induced Demyelination","authors":"S. Goudarzi, Andrea D Rivera, A. Butt, S. Hafizi","doi":"10.1177/1759091416668430","DOIUrl":"https://doi.org/10.1177/1759091416668430","url":null,"abstract":"A key aim of therapy for multiple sclerosis (MS) is to promote the regeneration of oligodendrocytes and remyelination in the central nervous system (CNS). The present study provides evidence that the vitamin K-dependent protein growth arrest specific 6 (Gas6) promotes such repair in in vitro cultures of mouse optic nerve and cerebellum. We first determined expression of Gas6 and TAM (Tyro3, Axl, Mer) receptors in the mouse CNS, with all three TAM receptors increasing in expression through postnatal development, reaching maximal levels in the adult. Treatment of cultured mouse optic nerves with Gas6 resulted in significant increases in oligodendrocyte numbers as well as expression of myelin basic protein (MBP). Gas6 stimulation also resulted in activation of STAT3 in optic nerves as well as downregulation of multiple genes involved in MS development, including matrix metalloproteinase-9 (MMP9), which may decrease the integrity of the blood–brain barrier and is found upregulated in MS lesions. The cytoprotective effects of Gas6 were examined in in vitro mouse cerebellar slice cultures, where lysolecithin was used to induce demyelination. Cotreatment of cerebellar slices with Gas6 significantly attenuated demyelination as determined by MBP immunostaining, and Gas6 activated Tyro3 receptor through its phosphorylation. In conclusion, these results demonstrate that Gas6/TAM signaling stimulates the generation of oligodendrocytes and increased myelin production via Tyro3 receptor in the adult CNS, including repair after demyelinating injury. Furthermore, the effects of Gas6 on STAT3 signaling and matrix MMP9 downregulation indicate potential glial cell repair and immunoregulatory roles for Gas6, indicating that Gas6-TAM signaling could be a potential therapeutic target in MS and other neuropathologies.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416668430","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65579304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Clock Genes in Glia Cells 神经胶质细胞中的时钟基因

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-09-01 DOI: 10.1177/1759091416670766

Donají Chi-Castañeda, A. Ortega

引用次数: 5

HIV-1 Tat Inhibits Autotaxin Lysophospholipase D Activity and Modulates Oligodendrocyte Differentiation 抑制自身taxin溶血磷脂酶D活性和调节少突胶质细胞分化的HIV-1 Tat

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-09-01 DOI: 10.1177/1759091416669618

Natalie A. Wheeler, B. Fuss, P. Knapp, S. Zou

{"title":"HIV-1 Tat Inhibits Autotaxin Lysophospholipase D Activity and Modulates Oligodendrocyte Differentiation","authors":"Natalie A. Wheeler, B. Fuss, P. Knapp, S. Zou","doi":"10.1177/1759091416669618","DOIUrl":"https://doi.org/10.1177/1759091416669618","url":null,"abstract":"White matter injury has been frequently reported in HIV+ patients. Previous studies showed that HIV-1 Tat (transactivator of transcription), a viral protein that is produced and secreted by HIV-infected cells, is toxic to young, immature oligodendrocytes (OLGs). Adding Tat to the culture medium reduced the viability of immature OLGs, and the surviving OLGs exhibited reduced process networks. OLGs produce and secrete autotaxin (ATX), an ecto-enzyme containing a lysophospholipase D (lysoPLD) activity that converts lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a lipid signaling molecule that stimulates OLG differentiation. We hypothesized that Tat affects OLG development by interfering with the ATX-LPA signaling pathway. Our data show that Tat treatment leads to changes in the expression of OLG differentiation genes and the area of OLG process networks, both of which can be rescued by LPA. Tat-treated OLGs showed no change in LPA receptor expression but significantly decreased extracellular ATX levels and lysoPLD activity. In Tat transgenic mice, expression of Tat in vivo leads to decreased OLG ATX secretion. Furthermore, co-immunoprecipitation experiments revealed a potential physical interaction between Tat and ATX. Together, these data strongly suggest two functional implications of Tat blocking ATX’s lysoPLD activity. On one hand, it attenuates OLG differentiation, and on the other hand it interferes with the protective effects of LPA on OLG process morphology.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416669618","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65579480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Photoperiod Modulates Fast Delayed Rectifier Potassium Currents in the Mammalian Circadian Clock 光周期调节哺乳动物生物钟中的快速延迟整流钾电流

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-09-01 DOI: 10.1177/1759091416670778

Sahar Farajnia, J. Meijer, S. Michel

{"title":"Photoperiod Modulates Fast Delayed Rectifier Potassium Currents in the Mammalian Circadian Clock","authors":"Sahar Farajnia, J. Meijer, S. Michel","doi":"10.1177/1759091416670778","DOIUrl":"https://doi.org/10.1177/1759091416670778","url":null,"abstract":"One feature of the mammalian circadian clock, situated in the suprachiasmatic nucleus (SCN), is its ability to measure day length and thereby contribute to the seasonal adaptation of physiology and behavior. The timing signal from the SCN, namely the 24 hr pattern of electrical activity, is adjusted according to the photoperiod being broader in long days and narrower in short days. Vasoactive intestinal peptide and gamma-aminobutyric acid play a crucial role in intercellular communication within the SCN and contribute to the seasonal changes in phase distribution. However, little is known about the underlying ionic mechanisms of synchronization. The present study was aimed to identify cellular mechanisms involved in seasonal encoding by the SCN. Mice were adapted to long-day (light–dark 16:8) and short-day (light–dark 8:16) photoperiods and membrane properties as well as K+ currents activity of SCN neurons were measured using patch-clamp recordings in acute slices. Remarkably, we found evidence for a photoperiodic effect on the fast delayed rectifier K+ current, that is, the circadian modulation of this ion channel’s activation reversed in long days resulting in 50% higher peak values during the night compared with the unaltered day values. Consistent with fast delayed rectifier enhancement, duration of action potentials during the night was shortened and afterhyperpolarization potentials increased in amplitude and duration. The slow delayed rectifier, transient K+ currents, and membrane excitability were not affected by photoperiod. We conclude that photoperiod can change intrinsic ion channel properties of the SCN neurons, which may influence cellular communication and contribute to photoperiodic phase adjustment.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416670778","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65579685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Enhanced Histochemical Detection of Iron in Paraffin Sections of Mouse Central Nervous System Tissue 小鼠中枢神经系统石蜡切片铁的强化组织化学检测

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-09-01 DOI: 10.1177/1759091416670978

S. Sands, R. Leung-Toung, Yingsheng Wang, J. Connelly, S. LeVine

{"title":"Enhanced Histochemical Detection of Iron in Paraffin Sections of Mouse Central Nervous System Tissue","authors":"S. Sands, R. Leung-Toung, Yingsheng Wang, J. Connelly, S. LeVine","doi":"10.1177/1759091416670978","DOIUrl":"https://doi.org/10.1177/1759091416670978","url":null,"abstract":"Histochemical methods of detecting iron in the rodent brain result mainly in the labeling of oligodendrocytes, but as all cells utilize iron, this observation suggests that much of the iron in the central nervous system goes undetected. Paraffin embedding of tissue is a standard procedure that is used to prepare sections for microscopic analysis. In the present study, we questioned whether we could modify the iron histochemical procedure to enable a greater detection of iron in paraffin sections. Indeed, various modifications led to the widespread labeling of iron in mouse brain tissue (for instance, labeling of neurons and neuropil). Sites of focal concentrations, such as cytoplasmic punctate or nucleolar staining, were also observed. The modified procedures were applied to paraffin sections of a mouse model (APP/PS1) of Alzheimer’s disease. Iron was revealed in the plaque core and rim. The plaque rim had a fibrillary or granular appearance, and it frequently contained iron-labeled cells. Further analysis indicated that the iron was tightly associated with the core of the plaque, but less so with the rim. In conclusion, modifications to the histochemical staining revealed new insights into the deposition of iron in the central nervous system. In theory, the approach should be transferrable to organs besides the brain and to other species, and the underlying principles should be incorporable into a variety of staining methods.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416670978","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65579801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 28

Anti-Sulfoglucuronosyl Paragloboside Antibody 抗磺脲醛基副叶苷抗体

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-09-01 DOI: 10.1177/1759091416669619

Dongpei Li, Seigo Usuki, Brandy M Quarles, Michael H. Rivner, T. Ariga, R. Yu

{"title":"Anti-Sulfoglucuronosyl Paragloboside Antibody","authors":"Dongpei Li, Seigo Usuki, Brandy M Quarles, Michael H. Rivner, T. Ariga, R. Yu","doi":"10.1177/1759091416669619","DOIUrl":"https://doi.org/10.1177/1759091416669619","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. Although the etiology of ALS is obscure, genetic studies of familiar ALS suggest a multifactorial etiology for this condition. Similarly, there probably are multiple causes for sporadic ALS. Autoimmune-mediated motor neuron dysfunction is one proposed etiology for sporadic ALS. In the present study, anti-glycolipid antibodies including GM1, GD1b, GD3, and sulfoglucuronosyl paragloboside (SGPG) were investigated in the sera of a large number of patient samples, including 113 ALS patients and 50 healthy controls, by means of enzyme-linked immunosorbent assay with affinity parametric complex criterion evaluation and thin-layer chromatography immunooverlay (immuno-TLC). Anti-SGPG antibodies were found in the sera of 13.3% ALS patients (15 out of 113). The highest titer reached 1:1600. The presence of anti-SGPG antibodies in the serum samples was also confirmed by immuno-TLC. Importantly, a multiple logistic regression analysis showed that the presence of anti-SGPG antibody was positively correlated with age (p < .01) and negatively correlated with ALS Functional Rating Scale score (p < .05). Moreover, the localization of SGPG-immunoreactivity on the motor neurons of rat spinal cord and a mouse motor neuronal cell line, NSC-34 was observed by an immunofluorescence method. These data suggest that SGPG could represent a specific pathogenic antigen in those ALS patients. The presence of anti-SGPG antibodies in the serum of ALS patients should represent a diagnostic biomarker of ALS, and it could reflect the severity of the disease.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 1","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416669619","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65579578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Increased Risk of Autism Development in Children Whose Mothers Experienced Birth Complications or Received Labor and Delivery Drugs. 母亲经历过分娩并发症或接受过分娩和分娩药物的儿童患自闭症的风险增加。

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-08-09 Print Date: 2016-08-01 DOI: 10.1177/1759091416659742

Melissa Smallwood, Ashley Sareen, Emma Baker, Rachel Hannusch, Eddy Kwessi, Tyisha Williams

{"title":"Increased Risk of Autism Development in Children Whose Mothers Experienced Birth Complications or Received Labor and Delivery Drugs.","authors":"Melissa Smallwood, Ashley Sareen, Emma Baker, Rachel Hannusch, Eddy Kwessi, Tyisha Williams","doi":"10.1177/1759091416659742","DOIUrl":"https://doi.org/10.1177/1759091416659742","url":null,"abstract":"Autism spectrum disorder (ASD) is a perplexing and pervasive developmental disorder characterized by social difficulties, communicative deficits, and repetitive behavior. The increased rate of ASD diagnosis has raised questions concerning the genetic and environmental factors contributing to the development of this disorder; meanwhile, the cause of ASD remains unknown. This study surveyed mothers of ASD and non-ASD children to determine possible effects of labor and delivery (L&D) drugs on the development of ASD. The survey was administered to mothers; however, the results were analyzed by child, as the study focused on the development of autism. Furthermore, an independent ASD dataset from the Southwest Autism Research and Resource Center was analyzed and compared. Indeed, L&D drugs are associated with ASD (p = .039). Moreover, the Southwest Autism Research and Resource Center dataset shows that the labor induction drug, Pitocin, is significantly associated with ASD (p = .004). We also observed a synergistic effect between administrations of L&D drugs and experiencing a birth complication, in which both obstetrics factors occurring together increased the likelihood of the fetus developing ASD later in life (p = .0003). The present study shows the possible effects of L&D drugs, such as Pitocin labor-inducing and analgesic drugs, on children and ASD.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 4","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416659742","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34745949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 19

Diffusible Factors Secreted by Glioblastoma and Medulloblastoma Cells Induce Oxidative Stress in Bystander Neural Stem Progenitors. 胶质母细胞瘤和髓母细胞瘤细胞分泌的扩散因子诱导旁观者神经干祖细胞氧化应激。

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-08-09 Print Date: 2016-08-01 DOI: 10.1177/1759091416662808

Neha Sharma, Nicholas W Colangelo, Sonia M de Toledo, Edouard I Azzam

{"title":"Diffusible Factors Secreted by Glioblastoma and Medulloblastoma Cells Induce Oxidative Stress in Bystander Neural Stem Progenitors.","authors":"Neha Sharma, Nicholas W Colangelo, Sonia M de Toledo, Edouard I Azzam","doi":"10.1177/1759091416662808","DOIUrl":"https://doi.org/10.1177/1759091416662808","url":null,"abstract":"Harmful effects that alter the homeostasis of neural stem or progenitor cells (NSPs) can affect regenerative processes in the central nervous system. We investigated the effect of soluble factors secreted by control or (137)Cs-γ-irradiated glioblastoma or medulloblastoma cells on redox-modulated endpoints in recipient human NSPs. Growth medium harvested from the nonirradiated brain tumor cells, following 24 h of growth, induced prominent oxidative stress in recipient NSPs as judged by overall increases in mitochondrial superoxide radical levels (p < .001), activation of c-jun N-terminal kinase, and decrease in the active form of FoxO3a. The induced oxidative stress was associated with phosphorylation of p53 on serine 15, a marker of DNA damage, induction of the cyclin-cyclin dependent kinase inhibitors p21(Waf1) and p27(Kip1), and perturbations in cell cycle progression (p < .001). These changes were also associated with increased apoptosis as determined by enhanced annexin V staining (p < .001) and caspase 8 activation (p < .05) and altered expression of critical regulators of self-renewal, proliferation, and differentiation. Exposure of the tumor cells to radiation only slightly altered the induced oxidative changes in the bystander NSPs, except for medium from irradiated medulloblastoma cells that was more potent at inducing apoptosis in the NSPs than medium from nonirradiated cells (p < .001). The elucidation of such stressful bystander effects provides avenues to understand the biochemical events underlying the development or exacerbation of degenerative outcomes associated with brain cancers. It is also relevant to tissue culture protocols whereby growth medium conditioned by tumor cells is often used to support the growth of stem cells.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 4","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416662808","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34745950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10

Repairing the Brain by SCF+G-CSF Treatment at 6 Months Postexperimental Stroke: Mechanistic Determination of the Causal Link Between Neurovascular Regeneration and Motor Functional Recovery. 脑卒中后6个月SCF+G-CSF治疗修复脑:神经血管再生与运动功能恢复之间因果关系的机制确定

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-08-09 Print Date: 2016-06-01 DOI: 10.1177/1759091416655010

Lili Cui, Dandan Wang, Sandra McGillis, Michele Kyle, Li-Ru Zhao

{"title":"Repairing the Brain by SCF+G-CSF Treatment at 6 Months Postexperimental Stroke: Mechanistic Determination of the Causal Link Between Neurovascular Regeneration and Motor Functional Recovery.","authors":"Lili Cui, Dandan Wang, Sandra McGillis, Michele Kyle, Li-Ru Zhao","doi":"10.1177/1759091416655010","DOIUrl":"https://doi.org/10.1177/1759091416655010","url":null,"abstract":"Stroke, a leading cause of adult disability in the world, is a severe medical condition with limited treatment. Physical therapy, the only treatment available for stroke rehabilitation, appears to be effective within 6 months post-stroke. Here, we have mechanistically determined the efficacy of combined two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF; SCF + G-CSF), in brain repair 6 months after cortical infarct induction in the transgenic mice carrying yellow fluorescent protein in Layer V pyramidal neurons (Thy1-YFP-H). Using a combination of live brain imaging, whole brain imaging, molecular manipulation, synaptic and vascular assessments, and motor function examination, we found that SCF + G-CSF promoted mushroom spine formation, enlarged postsynaptic membrane size, and increased postsynaptic density-95 accumulation and blood vessel density in the peri-infarct cavity cortex; and that SCF + G-CSF treatment improved motor functional recovery. The SCF + G-CSF-enhanced motor functional recovery was dependent on the synaptic and vascular regeneration in the peri-infarct cavity cortex. These data suggest that a stroke-damaged brain is repairable by SCF + G-CSF even 6 months after the lesion occurs. This study provides novel insights into the development of new restorative strategies for stroke recovery.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 4","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416655010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34745948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione. nadph缺失少突胶质前体细胞的抗氧化保护依赖于还原性谷胱甘肽的供应。

IF 4.7 4区医学

ASN NEURO Pub Date : 2016-07-21 Print Date: 2016-08-01 DOI: 10.1177/1759091416660404

Ewa Kilanczyk, Sujata Saraswat Ohri, Scott R Whittemore, Michal Hetman

{"title":"Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione.","authors":"Ewa Kilanczyk, Sujata Saraswat Ohri, Scott R Whittemore, Michal Hetman","doi":"10.1177/1759091416660404","DOIUrl":"https://doi.org/10.1177/1759091416660404","url":null,"abstract":"The pentose phosphate pathway is the main source of NADPH, which by reducing oxidized glutathione, contributes to antioxidant defenses. Although oxidative stress plays a major role in white matter injury, significance of NADPH for oligodendrocyte survival has not been yet investigated. It is reported here that the NADPH antimetabolite 6-amino-NADP (6AN) was cytotoxic to cultured adult rat spinal cord oligodendrocyte precursor cells (OPCs) as well as OPC-derived oligodendrocytes. The 6AN-induced necrosis was preceded by increased production of superoxide, NADPH depletion, and lower supply of reduced glutathione. Moreover, survival of NADPH-depleted OPCs was improved by the antioxidant drug trolox. Such cells were also protected by physiological concentrations of the neurosteroid dehydroepiandrosterone (10(-8) M). The protection by dehydroepiandrosterone was associated with restoration of reduced glutathione, but not NADPH, and was sensitive to inhibition of glutathione synthesis. A similar protective mechanism was engaged by the cAMP activator forskolin or the G protein-coupled estrogen receptor (GPER/GPR30) ligand G1. Finally, treatment with the glutathione precursor N-acetyl cysteine reduced cytotoxicity of 6AN. Taken together, NADPH is critical for survival of OPCs by supporting their antioxidant defenses. Consequently, injury-associated inhibition of the pentose phosphate pathway may be detrimental for the myelination or remyelination potential of the white matter. Conversely, steroid hormones and cAMP activators may promote survival of NADPH-deprived OPCs by increasing a NADPH-independent supply of reduced glutathione. Therefore, maintenance of glutathione homeostasis appears as a critical effector mechanism for OPC protection against NADPH depletion and preservation of the regenerative potential of the injured white matter.","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"8 4","pages":""},"PeriodicalIF":4.7,"publicationDate":"2016-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1759091416660404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34696875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22