83 results on '"Koziel V"'
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2. Characterization of adenosine receptors in a model of cultured neurons from rat forebrain
- Author
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Nicolas, F., Oillet, J., Koziel, V., and Daval, J. L.
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- 1994
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3. P4-271: Alpha-Synuclein Oligomer Preparations Induce Neurodegeneration and Cognitive Decline: a Novel Model for Parkinson’s DISEASE
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Pillot, Thierry, primary, Goetghebeur, P., additional, Rimet, D., additional, Fischer, N., additional, Terroire, Y., additional, Colin, S., additional, Allouche, A., additional, Koziel, V., additional, and Kopke, A.K.E., additional
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- 2016
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4. ALPHA-SYNUCLEIN OLIGOMER PREPARATIONS INDUCE NEURODEGENERATION AND COGNITIVE DECLINE: A NOVEL MODEL FOR PARKINSON’S DISEASE
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Pillot, Thierry, Goetghebeur, P., Rimet, D., Fischer, N., Terroire, Y., Colin, S., Allouche, A., Koziel, V., and Kopke, A.K.E.
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- 2016
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5. Ciliary Neurotrophic Factor Cell-Based Delivery Prevents Synaptic Impairment and Improves Memory in Mouse Models of Alzheimer's Disease
- Author
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Garcia, P., primary, Youssef, I., additional, Utvik, J. K., additional, Florent-Bechard, S., additional, Barthelemy, V., additional, Malaplate-Armand, C., additional, Kriem, B., additional, Stenger, C., additional, Koziel, V., additional, Olivier, J.-L., additional, Escanye, M.-C., additional, Hanse, M., additional, Allouche, A., additional, Desbene, C., additional, Yen, F. T., additional, Bjerkvig, R., additional, Oster, T., additional, Niclou, S. P., additional, and Pillot, T., additional
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- 2010
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6. Sequential expression patterns of apoptosis- and cell cycle-related proteins in neuronal response to severe or mild transient hypoxia
- Author
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Bossenmeyer-Pourié, C, primary, Lièvre, V, additional, Grojean, S, additional, Koziel, V, additional, Pillot, T, additional, and Daval, J.L, additional
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- 2002
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7. Intracellular generation of free radicals and modifications of detoxifying enzymes in cultured neurons from the developing rat forebrain in response to transient hypoxia
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Lièvre, V, primary, Becuwe, P, additional, Bianchi, A, additional, Bossenmeyer-Pourié, C, additional, Koziel, V, additional, Franck, P, additional, Nicolas, M.B, additional, Dauça, M, additional, Vert, P, additional, and Daval, J.L, additional
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- 2001
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8. Involvement of caspase-1 proteases in hypoxic brain injury. Effects of their inhibitors in developing neurons
- Author
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Bossenmeyer-Pourié, C, primary, Koziel, V, additional, and Daval, J.L, additional
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- 1999
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9. Intoxication cérébrale par la bilirubine chez le rat immature : effets sur le métabolisme énergétique et la perméabilité régionale
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Roger, C, primary, Koziel, V, additional, Humbert, A, additional, and Vert, P, additional
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- 1996
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10. Toxic effects of apomorphine on rat cultured neurons and glial C6 cells, and protection with antioxidants
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El-Bacha, R. dos Santos, Daval, J. L., Koziel, V., Netter, P., and Minn, A.
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- 2001
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11. Free radical production and changes in superoxide dismutases associated with hypoxia/reoxygenation-induced apoptosis of embryonic rat forebrain neurons in culture
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Lievre, V., Becuwe, P., Bianchi, A., Koziel, V., Franck, P., Schroeder, H., Nabet, P., Dauca, M., and Daval, J. L.
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- 2000
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12. Repeated seizure-associated long-lasting changes of N-methyl-d-aspartate receptor properties in the developing rat brain
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Doriat, J.-F., Koziel, V., Humbert, A.-C., and Daval, J.-L.
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- 1999
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13. Medium- and long-term alterations of brain A1 and A2A adenosine receptor characteristics following repeated seizures in developing rats
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Doriat, J.-F., Koziel, V., Humbert, A.-C., and Daval, J.-L.
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- 1999
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14. Medium- and long-term effects of repeated bicuculline-induced seizures in developing rats on local cerebral energy metabolism
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Doriat, J.-F., Koziel, V., Humbert, A.-C., and Daval, J.-L.
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- 1998
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15. Sequential activation of activator protein-1-related transcription factors and JNK protein kinases may contribute to apoptotic death induced by transient hypoxia in developing brain neurons
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Chihab, R., Ferry, C., Koziel, V., Monin, P., and Daval, Jean-Luc
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- 1998
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16. Mapping of the consequences of bilirubin exposure in the immature rat: local cerebral metabolic rates for glucose during moderate and severe hyperbilirubinemia
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Roger, C., Koziel, V., Vert, P., and Nehlig, A.
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- 1995
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17. Neuroprotective effects of DHA in Alzheimer’s disease models
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Florent-Béchard Sabrina, Koziel Violette, Olivier Jean-Luc, Oster Thierry, and Pillot Thierry
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Alzheimer’s disease ,docosahexaenoic acid ,neuronal membrane ,neuroprotection ,soluble Aβ oligomers ,Oils, fats, and waxes ,TP670-699 - Abstract
Alzheimer’s disease (AD) is a major public health concern in all developped countries. Although the precise cause of AD is still unknown, a growing body of evidence supports the notion that soluble oligomers of amyloid b-peptide (Aβ) may be the proximate effectors of synaptic injuries and neuronal death in the early stages of AD. AD patients display lower levels of docosahexaenoic acid (DHA, C22:6; n-3) in plasma and brain tissues as compared to control subjects of same age. Furthermore, epidemiological studies suggest that high DHA intake might have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that DHA-rich diets limit the synaptic loss and cognitive defects induced by Aβ peptide. Although the molecular basis underlying these neuroprotective effects remains unknown, several mechanisms have been proposed such as (i) regulation of the expression of potentially protective genes, (ii) activation of antiinflammatory pathways, (iii) modulation of functional properties of the synaptic membranes along with changes in their physicochemical and structural features. We recently demonstrated that DHA protects neurons from soluble Aβ oligomer-induced apoptosis. Indeed, DHA pretreatment was observed to significantly increase neuronal survival upon Aβ treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting ERK-related survival pathways. These data suggest that DHA enrichment most likely induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Aβ oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases.
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- 2007
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18. Acide docosahexaénoïque et maladie d’Alzheimer : des raisons d’espérer ?
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Florent-Bechard Sabrina, Youssef Ihsen, Malaplate-Armand Catherine, Koziel Violette, Leininger-Muller Brigitte, Kriem Badreddine, Olivier Jean-Luc, Oster Thierry, and Pillot Thierry
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Alzheimer’s disease ,docosahexaenoic acid ,public health ,Oils, fats, and waxes ,TP670-699 - Abstract
Alzheimer’s disease is a major public health concern in all developped countries. Although the precise cause of Alzheimer’s disease is still unknown, soluble oligomers of the neurotoxic hydrophobic amyloid-β (Aβ) peptide are known to play a critical role. Aging is associated with a loss of docosahexaenoic acid (DHA) in brain tissues in which it is the main polyunsaturated fatty acid. Epidemiological studies on human populations suggested that diets enriched in ω3 fatty acids are associated with reduced risk of Alzheimer’s disease. Furthermore, patients affected by Alzheimer’s disease display lower levels of DHA in plasma and brain tissues as compared to control subjects of same age. Studies on animals showed that diets enriched with DHA limit the synaptic loss and cognitive defects induced by the Aβ peptide. Several mechanisms have been proposed for this protective effects. DHA can induce the expression of potentially protective genes. Conversion of DHA into neuroprotectins has been shown to be alternatively involved in the protection against the Aβ peptide. Eventually, results have been provided suggesting that particular membrane microdomains could be remodelled and subsequently be involved in the neuroprotective process induced by DHA.
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- 2007
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19. Persistence of the Gastric Mucosa Inflammation After Fetal and Early Post-Natal Exposition to Methyl Donor Deficiency in the Rat
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Pourie, C., Daval, J. L., Pourie, G., Catherine Tomasetto, Helle, D., Koziel, V., Rio, M. C., Gueant, J. L., and Beck, B.
20. Regional cerebral metabolic consequences of bilirubin in rat depend upon post-gestational age at the time of hyperbilirubinemia
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Roger, C., Koziel, V., Vert, P., and Nehlig, A.
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- 1995
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21. Effects of bilirubin infusion on local cerebral glucose utilization in the immature rat
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Roger, C., Koziel, V., Vert, P., and Nehlig, A.
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- 1993
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22. Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat.
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Watremez W, Jackson J, Almari B, McLean SL, Grayson B, Neill JC, Fischer N, Allouche A, Koziel V, Pillot T, and Harte MK
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- Animals, Brain drug effects, Brain metabolism, Brain pathology, Cognition drug effects, Disease Models, Animal, Donepezil pharmacology, Female, Inflammation drug therapy, Inflammation pathology, Male, Memory Disorders drug therapy, Memory Disorders pathology, Neurons drug effects, Neurons pathology, Nootropic Agents pharmacology, Random Allocation, Rats, Recognition, Psychology drug effects, Recognition, Psychology physiology, Risperidone pharmacology, Rolipram pharmacology, Synapses drug effects, Synapses metabolism, Synapses pathology, Amyloid beta-Peptides metabolism, Cognition physiology, Inflammation metabolism, Memory Disorders metabolism, Neurons metabolism, Peptide Fragments metabolism, gamma-Aminobutyric Acid metabolism
- Abstract
Background: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies., Objective: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat., Methods: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus)., Results: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss., Conclusion: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.
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- 2018
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23. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.
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Daniels MJ, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, Booth SJ, White CS, Baldwin AG, Freeman S, Wong R, Latta C, Yu S, Jackson J, Fischer N, Koziel V, Pillot T, Bagnall J, Allan SM, Paszek P, Galea J, Harte MK, Eder C, Lawrence CB, and Brough D
- Subjects
- Alzheimer Disease metabolism, Animals, Bone Marrow Cells metabolism, Cell Death, Chloride Channels metabolism, Cysteine metabolism, Female, Genotype, Inflammation, Interleukin-1beta metabolism, Macrophages metabolism, Memory Disorders drug therapy, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Pattern Recognition, Visual drug effects, Rats, Alzheimer Disease prevention & control, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Flufenamic Acid pharmacology, Inflammasomes metabolism, Mefenamic Acid pharmacology, NLR Family, Pyrin Domain-Containing 3 Protein metabolism
- Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics.
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- 2016
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24. Folate- and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor α.
- Author
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Pourié G, Martin N, Bossenmeyer-Pourié C, Akchiche N, Guéant-Rodriguez RM, Geoffroy A, Jeannesson E, El Hajj Chehadeh S, Mimoun K, Brachet P, Koziel V, Alberto JM, Helle D, Debard R, Leininger B, Daval JL, and Guéant JL
- Subjects
- Animals, Brain embryology, Brain pathology, Early Growth Response Protein 1 metabolism, Estrogen Receptor alpha agonists, Estrogen Receptor alpha antagonists & inhibitors, Female, Neural Stem Cells metabolism, Neural Stem Cells pathology, PPAR gamma metabolism, Pregnancy, Rats, Brain metabolism, Estrogen Receptor alpha metabolism, Folic Acid Deficiency, Gene Expression Regulation, Developmental, Lactation, Synapsins biosynthesis, Vitamin B 12 Deficiency
- Abstract
Deficiency in the methyl donors vitamin B12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor α (ER-α)/Src tyrosine kinase. The influence of impaired ER-α pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-α antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-α and subsequent decreased ER-α/PPAR-γ coactivator 1 α (PGC-1α) interaction in deficiency condition. The impaired ER-α pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4-quinazolinamine, SKI-1, Src-l1) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-α pathway., (© FASEB.)
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- 2015
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25. Early methyl donor deficiency produces severe gastritis in mothers and offspring through N-homocysteinylation of cytoskeleton proteins, cellular stress, and inflammation.
- Author
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Bossenmeyer-Pourié C, Pourié G, Koziel V, Helle D, Jeannesson E, Guéant JL, and Beck B
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- Animals, Animals, Newborn, Animals, Suckling, Cadherins metabolism, Female, Fetus, Gastritis metabolism, Inflammation metabolism, Methylation, Mothers, Pregnancy, Rats, Rats, Wistar, Severity of Illness Index, Signal Transduction physiology, Cytoskeletal Proteins metabolism, Gastritis etiology, Gastritis pathology, Homocysteine metabolism, Inflammation etiology, Inflammation pathology, Oxidative Stress physiology
- Abstract
We examined the gastric mucosa structure and inflammatory status in control well-nourished Wistar dams and in Wistar dams deprived of choline, folate, and vitamin B12 during gestation and suckling periods, and in their offspring just before birth and at weaning. In this model of methyl donor deficiency (MDD), structural protein (E-cadherin and actin) N-homocysteinylation was measured through immunoprecipitation and proximity ligation assays. Cellular stress, inflammation, and apoptosis were estimated by the analysis of the NF-κB pathway, and the expression of superoxide dismutase, cyclooxygenase-2, tumor necrosis factor α, caspases 3 and 9, and TUNEL assay. Aberrant gastric mucosa formation and signs of surface layer erosion were detected in MDD fetuses and weanlings. E-cadherin and actin were N-homocysteinylated (+215 and +249% vs. controls, respectively; P<0.001). Expression of β-catenin staining drastically decreased (-98%; P<0.01). NF-κB pathway was activated (+124%; P<0.01). Expressions of all inflammatory factors (+70%; P<0.01), superoxide dismutase (+55%; P<0.01), and caspases (+104%; P<0.01) were markedly increased. These changes were also observed in dams, to a lesser extent. Early MDD induced gastric mucosa injury similar to atrophic gastritis through structural protein N-homocysteinylation, marked inflammation, and apoptosis, despite activation of repair machinery.
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- 2013
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26. Brain region-specific immunolocalization of the lipolysis-stimulated lipoprotein receptor (LSR) and altered cholesterol distribution in aged LSR+/- mice.
- Author
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Stenger C, Pinçon A, Hanse M, Royer L, Comte A, Koziel V, Olivier JL, Pillot T, and Yen FT
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- Age Factors, Animals, Choroid Plexus metabolism, Filipin metabolism, Gene Expression Regulation genetics, Glial Fibrillary Acidic Protein metabolism, Male, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphopyruvate Hydratase metabolism, Receptors, LDL deficiency, Aging metabolism, Brain cytology, Brain metabolism, Cholesterol metabolism, Neurons metabolism, Receptors, LDL metabolism
- Abstract
Brain lipid homeostasis is important for maintenance of brain cell function and synaptic communications, and is intimately linked to age-related cognitive decline. Because of the blood-brain barrier's limiting nature, this tissue relies on a complex system for the synthesis and receptor-mediated uptake of lipids between the different networks of neurons and glial cells. Using immunofluorescence, we describe the region-specific expression of the lipolysis-stimulated lipoprotein receptor (LSR), in the mouse hippocampus, cerebellum Purkinje cells, the ependymal cell interface between brain parenchyma and cerebrospinal fluid, and the choroid plexus. Colocalization with cell-specific markers revealed that LSR was expressed in neurons, but not astrocytes. Latency in arms of the Y-maze exhibited by young heterozygote LSR(+/-) mice was significantly different as compared to control LSR(+/+), and increased in older LSR(+/-) mice. Filipin and Nile red staining revealed membrane cholesterol content accumulation accompanied by significantly altered distribution of LSR in the membrane, and decreased intracellular lipid droplets in the cerebellum and hippocampus of old LSR(+/-) mice, as compared to control littermates as well as young LSR(+/-) animals. These data therefore suggest a potential role of LSR in brain cholesterol distribution, which is particularly important in preserving neuronal integrity and thereby cognitive functions during aging., (© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.)
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- 2012
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27. Homocysteinylation of neuronal proteins contributes to folate deficiency-associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells.
- Author
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Akchiche N, Bossenmeyer-Pourié C, Kerek R, Martin N, Pourié G, Koziel V, Helle D, Alberto JM, Ortiou S, Camadro JM, Léger T, Guéant JL, and Daval JL
- Subjects
- Animals, Blotting, Western, Cell Differentiation drug effects, Cell Line, Cell Movement drug effects, Cell Survival drug effects, Cells, Cultured, Hep G2 Cells, Humans, Immunohistochemistry, Neurons metabolism, Protein Binding, Rats, Rats, Wistar, Real-Time Polymerase Chain Reaction, Vitamin B 12 pharmacology, Folic Acid pharmacology, Folic Acid Deficiency metabolism, Hippocampus cytology, Homocysteine pharmacology, Neurons cytology, Neurons drug effects
- Abstract
Despite the key role in neuronal development of a deficit in the methyl donor folate, little is known on the underlying mechanisms. We therefore studied the consequences of folate deficiency on proliferation, differentiation, and plasticity of the rat H19-7 hippocampal cell line. Folate deficit reduced proliferation (17%) and sensitized cells to differentiation-associated apoptosis (+16%). Decreased production (-58%) of S-adenosylmethionine (the universal substrate for transmethylation reactions) and increased expression of histone deacetylases (HDAC4,6,7) would lead to epigenomic changes that may impair the differentiation process. Cell polarity, vesicular transport, and synaptic plasticity were dramatically affected, with poor neurite outgrowth (-57%). Cell treatment by an HDAC inhibitor (SAHA) led to a noticeable improvement of cell polarity and morphology, with longer processes. Increased homocysteine levels (+55%) consecutive to folate shortage produced homocysteinylation, evidenced by coimmunoprecipitations and mass spectrometry, and aggregation of motor proteins dynein and kinesin, along with functional alterations, as reflected by reduced interactions with partner proteins. Prominent homocysteinylation of key neuronal proteins and subsequent aggregation certainly constitute major adverse effects of folate deficiency, affecting normal development with possible long-lasting consequences.
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- 2012
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28. Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit.
- Author
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Desbène C, Malaplate-Armand C, Youssef I, Garcia P, Stenger C, Sauvée M, Fischer N, Rimet D, Koziel V, Escanyé MC, Oster T, Kriem B, Yen FT, Pillot T, and Olivier JL
- Subjects
- Animals, Cells, Cultured, Male, Maze Learning drug effects, Maze Learning physiology, Memory Disorders chemically induced, Mice, Mice, Inbred BALB C, Mice, Knockout, Neurodegenerative Diseases chemically induced, Amyloid beta-Peptides toxicity, Memory Disorders enzymology, Memory Disorders genetics, Neurodegenerative Diseases enzymology, Peptide Fragments toxicity, Phospholipases A2, Cytosolic physiology
- Abstract
Soluble beta-amyloid (Aβ) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that Aβ oligomers activate cytosolic phospholipase A(2) (cPLA(2)), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA(2) gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of Aβ oligomers in wild type mice. We further demonstrated that the Aβ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA(2)(-/-) mice. Interestingly, expression of the Aβ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA(2)(-/-) mice, but the relationship with the resistance of these mice to the Aβ oligomer toxicity requires further investigation. These results therefore show that cPLA(2) plays a key role in the Aβ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
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29. Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.
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Martin N, Bossenmeyer-Pourié C, Koziel V, Jazi R, Audonnet S, Vert P, Guéant JL, Daval JL, and Pourié G
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- Aging metabolism, Animals, Animals, Newborn, Blood Gas Analysis, Brain metabolism, Brain pathology, Cell Death, Cell Proliferation, Cell Survival, Female, Hypoxia blood, Hypoxia metabolism, Hypoxia pathology, Locomotion physiology, Male, Memory physiology, Neurogenesis, Neuronal Plasticity physiology, Rats, Rats, Wistar, Synapses metabolism, Aging physiology, Brain physiopathology, Hypoxia physiopathology
- Abstract
Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min) on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP) kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.
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- 2012
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30. Up-regulation of hepatic lipolysis stimulated lipoprotein receptor by leptin: a potential lever for controlling lipid clearance during the postprandial phase.
- Author
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Stenger C, Hanse M, Pratte D, Mbala ML, Akbar S, Koziel V, Escanyé MC, Kriem B, Malaplate-Armand C, Olivier JL, Oster T, Pillot T, and Yen FT
- Subjects
- Animals, Blotting, Western, Body Weight drug effects, Cell Line, Fluorescent Antibody Technique, Leptin blood, Liver metabolism, Mice, Mice, Inbred C57BL, Polymerase Chain Reaction, Leptin pharmacology, Lipid Metabolism drug effects, Lipolysis drug effects, Liver drug effects, Postprandial Period, Receptors, Lipoprotein metabolism, Up-Regulation drug effects
- Abstract
As a hepatic receptor for triglyceride-rich lipoproteins, the lipolysis-stimulated lipoprotein receptor (LSR) may be involved in the dynamics of lipid distribution between the liver and peripheral tissues. Here, we explore the potential role of leptin in regulating LSR. At physiological concentrations (1-10 ng/ml), leptin increased LSR protein and mRNA levels in Hepa1-6 cells through an ERK1/2-dependent and α-amanitin-sensitive pathway. In vivo, leptin treatment of C57BL6/Rj mice (1 μg 2×/d, 8 d) led to a significant increase in hepatic LSR mRNA and protein, decreased liver triglycerides and increased VLDL secretion as compared to controls. LSR(+/-) mice with elevated postprandial lipemia placed on a high-fat (60% kcal) diet exhibited accelerated weight gain and increased fat mass as compared to controls. While plasma leptin levels were increased 3-fold, hepatic leptin receptor protein levels and phosphorylation of ERK1/2 were significantly reduced. Therefore, leptin is an important regulator of LSR protein levels providing the means for the control of hepatic uptake of lipids during the postprandial phase. However, this may no longer be functional in LSR(+/-) mice placed under a chronic dietary fat load, suggesting that this animal model could be useful for the study of molecular mechanisms involved in peripheral leptin resistance.
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- 2010
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31. Differentiation and neural integration of hippocampal neuronal progenitors: signaling pathways sequentially involved.
- Author
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Akchiche N, Bossenmeyer-Pourié C, Pourié G, Koziel V, Nédélec E, Guéant JL, and Daval JL
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- Adenosine Triphosphate metabolism, Animals, Apoptosis drug effects, Bromodeoxyuridine metabolism, Caspases metabolism, Cell Differentiation drug effects, Cell Proliferation drug effects, Cells, Cultured, Coculture Techniques methods, Disks Large Homolog 4 Protein, Embryo, Mammalian, Enzyme Inhibitors pharmacology, Gene Expression Regulation drug effects, Imidazoles pharmacology, Intercellular Signaling Peptides and Proteins pharmacology, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Mitochondrial Membranes physiology, Mitogen-Activated Protein Kinase Kinases metabolism, Neurons drug effects, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Rats, Rats, Wistar, Signal Transduction drug effects, Stem Cells drug effects, Time Factors, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Vesicular Glutamate Transport Protein 2 genetics, Vesicular Glutamate Transport Protein 2 metabolism, bcl-X Protein genetics, bcl-X Protein metabolism, Cell Differentiation physiology, Hippocampus cytology, Neurons physiology, Signal Transduction physiology, Stem Cells physiology
- Abstract
In the context of their potential implication in regenerative strategies, we characterized cell mechanisms underlying the fate of embryonic rat hippocampal H19-7 progenitors in culture upon induction of their differentiation, and tested their capacities to integrate into a neuronal network in vitro. Without addition of growth factors, nearly 100% of cells expressed various neuronal markers, with a progressive rise of the expression of Synapsin I and II, suggesting that cells developed as mature neurons with synaptogenic capacities. Fully differentiated neurons were identified as glutamatergic and expressed the receptor-associated protein PSD-95. Quantification of ATP showed that 60% of cells died within 24 h after differentiation. Cell death was shown to imply Erk1/2-dependent intrinsic mitochondrial apoptosis signaling pathway, with activation of caspase-9 and -3, finally leading to single-strand DNA. Surviving neurons displayed high levels of Akt, phospho-Akt, and antiapoptotic proteins such as Bcl-2 and Bcl-XL, with decreased caspase activation. In the absence of trophic support, the proapoptotic death-associated protein (DAP) kinase was dramatically stimulated by 24 h postdifferentiation, along with increased levels of p38 and phospho-p38, and caspase reactivation. These findings show that different signaling pathways are sequentially triggered by differentiation, and highlight that ultimate cell death would involve p38 and DAP kinase activation. This was supported by the improvement of cell survival at 24-h postdifferentiation when cells were treated by PD169316, a specific inhibitor of p38. Finally, when seeded on rat hippocampal primary cultured neurons, a significant number of differentiated H19-7 cells were able to survive and to develop cell-cell communication., (Copyright 2009 Wiley-Liss, Inc.)
- Published
- 2010
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32. Methyl donor deficiency affects fetal programming of gastric ghrelin cell organization and function in the rat.
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Bossenmeyer-Pourié C, Blaise S, Pourié G, Tomasetto C, Audonnet S, Ortiou S, Koziel V, Rio MC, Daval JL, Guéant JL, and Beck B
- Subjects
- Animals, Body Weight, Cell Lineage, Choline metabolism, Enteroendocrine Cells metabolism, Female, Folic Acid metabolism, Ghrelin blood, Growth Hormone blood, Homocysteine blood, Immunohistochemistry, Pregnancy, Rats, Rats, Wistar, Vitamin B 12 metabolism, Weaning, Deficiency Diseases embryology, Deficiency Diseases physiopathology, Fetal Development, Gastric Mucosa metabolism, Gastric Mucosa pathology, Ghrelin metabolism
- Abstract
Methyl donor deficiency (MDD) during pregnancy influences intrauterine development. Ghrelin is expressed in the stomach of fetuses and influences fetal growth, but MDD influence on gastric ghrelin is unknown. We examined the gastric ghrelin system in MDD-induced intrauterine growth retardation. By using specific markers and approaches (such as periodic acid-Schiff, bromodeoxyuridine, homocysteine, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, immunostaining, reverse transcription-polymerase chain reaction), we studied the gastric oxyntic mucosa cellular organization and ghrelin gene expression in the mucosa in 20-day-old fetuses and weanling pups, and plasma ghrelin concentration in weanling rat pups of dams either normally fed or deprived of choline, folate, vitamin B6, and vitamin B12 during gestation and suckling periods. MDD fetuses weighed less than controls; the weight deficit reached 57% at weaning (P < 0.001). Both at the end of gestation and at weaning, they presented with an aberrant gastric oxyntic mucosa formation with loss of cell polarity, anarchic cell migration, abnormal progenitor differentiation, apoptosis, and signs of surface layer erosion. Ghrelin cells were abnormally located in the pit region of oxyntic glands. At weaning, plasma ghrelin levels were decreased (-28%; P < 0.001) despite unchanged mRNA expression in the stomach. This decrease was associated with lower body weight. Taken together, these data indicate that one mechanism through which MDD influences fetal programming is the remodeling of gastric cellular organization, leading to dysfunction of the ghrelin system and dramatic effects on growth.
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- 2010
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33. The essential role of lipids in Alzheimer's disease.
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Florent-Béchard S, Desbène C, Garcia P, Allouche A, Youssef I, Escanyé MC, Koziel V, Hanse M, Malaplate-Armand C, Stenger C, Kriem B, Yen-Potin FT, Olivier JL, Pillot T, and Oster T
- Subjects
- Alzheimer Disease pathology, Alzheimer Disease physiopathology, Animals, Apoptosis physiology, Fatty Acids, Omega-3 metabolism, Humans, Membrane Microdomains metabolism, Models, Biological, Signal Transduction physiology, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Lipid Metabolism physiology
- Abstract
In the absence of efficient diagnostic and therapeutic tools, Alzheimer's disease (AD) is a major public health concern due to longer life expectancy in the Western countries. Although the precise cause of AD is still unknown, soluble beta-amyloid (Abeta) oligomers are considered the proximate effectors of the synaptic injury and neuronal death occurring in the early stages of AD. Abeta oligomers may directly interact with the synaptic membrane, leading to impairment of synaptic functions and subsequent signalling pathways triggering neurodegeneration. Therefore, membrane structure and lipid status should be considered determinant factors in Abeta-oligomer-induced synaptic and cell injuries, and therefore AD progression. Numerous epidemiological studies have highlighted close relationships between AD incidence and dietary patterns. Among the nutritional factors involved, lipids significantly influence AD pathogenesis. It is likely that maintenance of adequate membrane lipid content could prevent the production of Abeta peptide as well as its deleterious effects upon its interaction with synaptic membrane, thereby protecting neurons from Abeta-induced neurodegeneration. As major constituents of neuronal lipids, n-3 polyunsaturated fatty acids are of particular interest in the prevention of AD valuable diet ingredients whose neuroprotective properties could be essential for designing preventive nutrition-based strategies. In this review, we discuss the functional relevance of neuronal membrane features with respect to susceptibility to Abeta oligomers and AD pathogenesis, as well as the prospective capacities of lipids to prevent or to delay the disease.
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- 2009
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34. N-truncated amyloid-beta oligomers induce learning impairment and neuronal apoptosis.
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Youssef I, Florent-Béchard S, Malaplate-Armand C, Koziel V, Bihain B, Olivier JL, Leininger-Muller B, Kriem B, Oster T, and Pillot T
- Subjects
- Animals, Apoptosis drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred C57BL, Amyloid beta-Peptides administration & dosage, Maze Learning drug effects, Neurons drug effects, Neurons pathology, Peptide Fragments administration & dosage
- Abstract
N-terminal-truncated forms of amyloid-beta (A beta) peptide have been recently suggested to play a pivotal role early in Alzheimer's disease (AD). Among them, A beta 3(pE)-42 peptide, starting with pyroglutamyl at residue Glu-3, is considered as the predominant A beta species in AD plaques and pre-amyloid lesions. Its abundance is reported to be directly proportional to the severity of the clinical phenotype. The present study investigates the effects of soluble oligomeric A beta 3(pE)-42 after intracerebroventricular injection on mice learning ability and the molecular mechanisms of its in vitro neurotoxicity. Mice injected with soluble A beta 3(pE)-42 or A beta(l-42) displayed impaired spatial working memory and delayed memory acquisition in Y-maze and Morris water maze tests, while those injected with soluble A beta(42-1) showed no effect. These cognitive alterations were associated with free radical overproduction in the hippocampus and olfactory bulbs, but not in the cerebral cortex or cerebellum. In vitro, A beta 3(pE)-42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pro-inflammatory pathway. These data suggest that A beta 3(pE)-42 could mediate the neurodegenerative process and subsequent cognitive alteration occurring in preclinical AD stages.
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- 2008
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35. Towards a nutritional approach for prevention of Alzheimer's disease: biochemical and cellular aspects.
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Florent-Béchard S, Malaplate-Armand C, Koziel V, Kriem B, Olivier JL, Pillot T, and Oster T
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- Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Animals, Brain physiopathology, Docosahexaenoic Acids metabolism, Encephalitis metabolism, Encephalitis physiopathology, Food, Formulated standards, Humans, Lipid Metabolism drug effects, Lipid Metabolism physiology, Neuroprotective Agents metabolism, Synapses drug effects, Synapses metabolism, Alzheimer Disease diet therapy, Alzheimer Disease prevention & control, Amyloid beta-Peptides antagonists & inhibitors, Brain drug effects, Brain metabolism, Docosahexaenoic Acids therapeutic use, Encephalitis diet therapy, Neuroprotective Agents therapeutic use
- Abstract
Alzheimer's disease (AD) is a major public health concern in all countries. Although the precise cause of AD is still unknown, a growing body of evidence supports the notion that soluble amyloid beta-peptide (Abeta) may be the proximate cause of synaptic injuries and neuronal death early in the disease. AD patients display lower levels of docosahexaenoic acid (DHA, C22:6 ; n-3) in plasma and brain tissues as compared to age-matched controls. Furthermore, epidemiological studies suggest that high DHA intake might have protective properties against neurodegenerative diseases. These observations are supported by in vivo studies showing that DHA-rich diets limits the synaptic loss and cognitive defects induced by Abeta peptide. Although the molecular basis of these neuroprotective effects remains unknown, several mechanisms have been proposed such as (i) regulation of the expression of potentially protective genes, (ii) activation of anti-inflammatory pathways, (iii) modulation of functional properties of the synaptic membranes along with changes in their physicochemical and structural features.
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- 2007
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36. Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway.
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Malaplate-Armand C, Florent-Béchard S, Youssef I, Koziel V, Sponne I, Kriem B, Leininger-Muller B, Olivier JL, Oster T, and Pillot T
- Subjects
- Animals, Apoptosis drug effects, Arachidonic Acid pharmacology, Enzyme Activation drug effects, Enzyme Activation physiology, Enzyme Inhibitors pharmacology, Lysophospholipids, Neurons drug effects, Neurons metabolism, Oligonucleotides, Antisense, Oxidation-Reduction, Phospholipases A2, Rats, Reactive Oxygen Species metabolism, Signal Transduction physiology, Sphingosine analogs & derivatives, Amyloid beta-Peptides metabolism, Apoptosis physiology, Ceramides metabolism, Neurons pathology, Phospholipases A metabolism, Sphingomyelin Phosphodiesterase metabolism
- Abstract
Recent data have revealed that soluble oligomeric amyloid-beta peptide (Abeta) may be the proximate effectors of neuronal injuries and death in Alzheimer's disease (AD) by unknown mechanisms. Consistently, we recently demonstrated the critical role of a redox-sensitive cytosolic calcium-dependent phospholipase A2 (cPLA2)-arachidonic acid (AA) pathway in Abeta oligomer-induced cell death. According to the involvement of oxidative stress and polyunsaturated fatty acids like AA in the regulation of sphingomyelinase (SMase) activity, the present study underlines the role of SMases in soluble Abeta-induced apoptosis. Soluble Abeta oligomers induced the activation of both neutral and acidic SMases, as demonstrated by the direct measurement of their enzymatic activities, by the inhibitory effects of both specific neutral and acidic SMase inhibitors, and by gene knockdown using antisense oligonucleotides. Furthermore, soluble Abeta-mediated activation of SMases and subsequent cell death were found to be inhibited by antioxidant molecules and a cPLA2-specific inhibitor or antisense oligonucleotide. We also demonstrate that sphingosine-1-phosphate is a potent neuroprotective factor against soluble Abeta oligomer-induced cell death and apoptosis by inhibiting soluble Abeta-induced activation of acidic sphingomyelinase. These results suggest that Abeta oligomers induce neuronal death by activating neutral and acidic SMases in a redox-sensitive cPLA2-AA pathway.
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- 2006
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37. Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronal apoptosis. Synergistic involvement of calpain and caspase-3.
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Fifre A, Sponne I, Koziel V, Kriem B, Yen Potin FT, Bihain BE, Olivier JL, Oster T, and Pillot T
- Subjects
- Animals, Apoptosis physiology, Calcium metabolism, Calpain metabolism, Caspase 3, Caspase 9, Caspases metabolism, Cells, Cultured, Cerebral Cortex cytology, Cytoskeleton drug effects, Cytoskeleton metabolism, Homeostasis drug effects, Isomerism, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins chemistry, Oxidative Stress physiology, Amyloid beta-Peptides toxicity, Apoptosis drug effects, Microtubule-Associated Proteins metabolism, Neurons cytology, Neurons metabolism, Peptide Fragments toxicity
- Abstract
A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid beta-peptide (Abeta) may be the proximate effectors of neuronal injuries and death in the early stages of Alzheimer disease. However, the molecular mechanisms associated with neuronal apoptosis induced by soluble Abeta remain to be elucidated. We recently demonstrated the involvement of an early reactive oxygen species-dependent perturbation of the microtubule network (Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pincon-Raymond, M., Olivier, J.-L., Chambaz, J., and Pillot, T. (2003) J. Biol. Chem. 278, 3437-3445). Because microtubule-associated proteins (MAPs) are responsible for the polymerization, stabilization, and dynamics of the microtubule network, we investigated whether MAPs might represent the intracellular targets that would enable us to explain the microtubule perturbation involved in soluble Abeta-mediated neuronal apoptosis. The data presented here show that soluble Abeta oligomers induce a time-dependent degradation of MAP1A, MAP1B, and MAP2 involving a perturbation of Ca2+ homeostasis with subsequent calpain activation that, on its own, is sufficient to induce the proteolysis of isoforms MAP2a, MAP2b, and MAP2c. In contrast, MAP1A and MAP1B sequential proteolysis results from the Abeta-mediated activation of caspase-3 and calpain. The prevention of MAP1A, MAP1B, and MAP2 proteolysis by antioxidants highlights the early reactive oxygen species generation in the perturbation of the microtubule network induced by soluble Abeta. These data clearly demonstrate the impact of cytoskeletal perturbations on soluble Abeta-mediated cell death and support the notion of microtubule-stabilizing agents as effective Alzheimer disease drugs.
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- 2006
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38. Docosahexaenoic acid prevents neuronal apoptosis induced by soluble amyloid-beta oligomers.
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Florent S, Malaplate-Armand C, Youssef I, Kriem B, Koziel V, Escanyé MC, Fifre A, Sponne I, Leininger-Muller B, Olivier JL, Pillot T, and Oster T
- Subjects
- Animals, Caspases metabolism, Cells, Cultured, Cerebral Cortex cytology, Cytoskeleton drug effects, Cytosol enzymology, Enzyme Activation drug effects, Fatty Acids, Omega-3 pharmacology, Oligodendroglia physiology, Oxidative Stress drug effects, Phospholipases A metabolism, Rats, Rats, Wistar, Solubility, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides pharmacology, Apoptosis drug effects, Docosahexaenoic Acids pharmacology, Neurons physiology, Neuroprotective Agents pharmacology
- Abstract
A growing body of evidence supports the notion that soluble oligomers of amyloid-beta (Abeta) peptide interact with the neuronal plasma membrane, leading to cell injury and inducing death-signalling pathways that could account for the increased neurodegeneration occurring in Alzheimer's disease (AD). Docosahexaenoic acid (DHA, C22:6, n-3) is an essential polyunsaturated fatty acid in the CNS and has been shown in several epidemiological and in vivo studies to have protective effects against AD and cognitive alterations. However, the molecular mechanisms involved remain unknown. We hypothesized that DHA enrichment of plasma membranes could protect neurones from apoptosis induced by soluble Abeta oligomers. DHA pre-treatment was observed to significantly increase neuronal survival upon Abeta treatment by preventing cytoskeleton perturbations, caspase activation and apoptosis, as well as by promoting extracellular signal-related kinase (ERK)-related survival pathways. These data suggest that DHA enrichment probably induces changes in neuronal membrane properties with functional outcomes, thereby increasing protection from soluble Abeta oligomers. Such neuroprotective effects could be of major interest in the prevention of AD and other neurodegenerative diseases.
- Published
- 2006
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39. Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-beta peptide.
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Kriem B, Sponne I, Fifre A, Malaplate-Armand C, Lozac'h-Pillot K, Koziel V, Yen-Potin FT, Bihain B, Oster T, Olivier JL, and Pillot T
- Subjects
- Animals, Arachidonic Acid metabolism, Cells, Cultured, Cerebral Cortex cytology, Cyclooxygenase 2, Humans, Membrane Proteins, Mitogen-Activated Protein Kinases metabolism, Phospholipases A2, Prostaglandin-Endoperoxide Synthases metabolism, Rats, Solubility, Amyloid beta-Peptides metabolism, Apoptosis physiology, Cytosol enzymology, Neurons enzymology, Neurons physiology, Peptide Fragments metabolism, Phospholipases A metabolism
- Abstract
Recent data have revealed that soluble oligomeric forms of amyloid peptide (Abeta) may be the proximate effectors of the neuronal injury and death occurring in Alzheimer's disease (AD). However, the molecular mechanisms associated with the neuronal cell death induced by the nonfibrillar Abeta remain to be elucidated. In this study, we investigated the role of the cytosolic Ca2+-dependent phospholipase A2 (cPLA2), and its associated metabolic pathway, i.e., the arachidonic acid (AA) cascade, in the apoptotic cell death induced by soluble oligomers of Abeta. The treatment of rat cortical neurons with low concentrations of soluble Abeta(1-40) or Abeta(1-42) peptide resulted in an early calcium-dependent release of AA associated with a transient relocalization of cPLA2. Both cPLA2 antisense oligonucleotides and a selective inhibitor of cPLA2 activity abolished the release of AA from neurons and also protected cells against apoptosis induced by Abeta. Furthermore, inhibitors of the PKC, p38, and MEK/ERK pathways that are involved in cPLA2 phosphorylation and activation reduced Abeta-induced cell death. Finally, we demonstrate that inhibitors of cyclooxygenase-2 reduced the Abeta-induced cell death by 55%. Our studies suggest a novel neuronal response of soluble oligomers of Abeta, which occurs through a cPLA2 signaling cascade and an AA-dependent death pathway. This may prove to be crucial in AD processes and could provide important targets for drug development.
- Published
- 2005
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40. Oligodendrocytes are susceptible to apoptotic cell death induced by prion protein-derived peptides.
- Author
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Sponne I, Fifre A, Koziel V, Kriem B, Oster T, Olivier JL, and Pillot T
- Subjects
- Animals, Animals, Newborn, Antioxidants pharmacology, Caspases drug effects, Caspases metabolism, Cell Membrane metabolism, Cells, Cultured, DNA Fragmentation drug effects, DNA Fragmentation physiology, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Myelin Sheath drug effects, Myelin Sheath pathology, Oligodendroglia drug effects, Oligodendroglia pathology, Oxidative Stress drug effects, Oxidative Stress physiology, Peptide Fragments toxicity, PrPC Proteins metabolism, Prion Diseases pathology, Prion Diseases physiopathology, Prions toxicity, Protein Structure, Tertiary physiology, Rats, Rats, Wistar, Apoptosis drug effects, Myelin Sheath metabolism, Oligodendroglia metabolism, Peptide Fragments metabolism, Prion Diseases metabolism, Prions metabolism
- Abstract
Neurodegenerative prion diseases, characterized by a progressive dementia, are associated with the accumulation of abnormal forms of the prion (PrPc) protein, potentially due to an aberrant regulation of PrPc biogenesis and/or topology. One of these forms, termed ctmPrP, displays a transmembrane conformation and might trigger neuronal cell death in Gerstmann-Straüssler-Scheinker (GSS) syndrome and other prion-associated diseases in humans. Although the primary target cells involved in the progression of prion diseases remain unidentified, it was recently suggested that modifications of the oligodendroglial cells occur early in prion diseases. In the present study, we demonstrate that a putative transmembrane domain of the human PrPc, i.e., amino acids 118-135, induces oligodendrocyte (OLG) death in vitro in a time- and dose-dependent manner. The process leading to OLG death and induced by the PrP[118-135] peptide was characterized by DNA fragmentation, cytoskeletal disruption, and caspase activation. Protection against the PrP[118-135] peptide-induced OLG apoptosis by several antioxidant molecules, such as probucol, propylgallate, and promethazine, suggests that oxidative injuries contribute to the PrP[118-135] cytotoxicity to OLGs. These results suggest a potential pathophysiological role of the ctmPrP- and/or PrP fragment-mediated OLG cytotoxicity in spongiform encephalopathies., (Copyright 2004 Wiley-Liss, Inc.)
- Published
- 2004
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41. Membrane cholesterol interferes with neuronal apoptosis induced by soluble oligomers but not fibrils of amyloid-beta peptide.
- Author
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Sponne I, Fifre A, Koziel V, Oster T, Olivier JL, and Pillot T
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides pharmacology, Amyloid beta-Peptides toxicity, Animals, Biopolymers, Caspase 8, Caspases metabolism, Cells, Cultured drug effects, Cells, Cultured ultrastructure, Cerebral Cortex cytology, Cerebral Cortex embryology, Cytoskeleton drug effects, Cytoskeleton ultrastructure, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Lipid Bilayers, Liposomes, Membrane Fluidity, Membrane Fusion drug effects, Neurons ultrastructure, Oxidative Stress, Peptide Fragments pharmacology, Peptide Fragments toxicity, Protein Conformation, Rats, Rats, Wistar, Solubility, Amyloid beta-Peptides antagonists & inhibitors, Apoptosis drug effects, Cholesterol pharmacology, Membrane Lipids pharmacology, Neurons drug effects, Peptide Fragments antagonists & inhibitors
- Abstract
Neuronal cell death in Alzheimer's disease (AD) is partly induced by the interaction of the amyloid-beta peptide (Abeta) with the plasma membrane of target cells. Accordingly, recent studies have suggested that cholesterol, an important component of membranes that controls their physical properties and functions, plays a critical role in neurodegenerative diseases. We report here that the enrichment of the neuronal plasma membrane with cholesterol protects cortical neurons from apoptosis induced by soluble oligomers of the Abeta(1-40) peptide. Conversely, cholesterol depletion using cyclodextrin renders cells more vulnerable to the cytotoxic effects of the Abeta-soluble oligomers. Increasing the cholesterol content of small unilamellar liposomes also decreases Abeta-dependent liposome fusion. We clearly demonstrate that cholesterol protection is specific to the soluble conformation of Abeta, because we observed no protective effects on cortical neurons treated by amyloid fibrils of the Abeta(1-40) peptide. This may provide a new opportunity for the development of an effective AD therapy as well as elucidate the impact of the cholesterol level during AD development.
- Published
- 2004
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42. Humanin rescues cortical neurons from prion-peptide-induced apoptosis.
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Sponne I, Fifre A, Koziel V, Kriem B, Oster T, and Pillot T
- Subjects
- Animals, Apoptosis drug effects, Cell Survival drug effects, Cell Survival physiology, Cells, Cultured, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cerebral Cortex pathology, Fetus, Intracellular Signaling Peptides and Proteins, Nerve Degeneration drug therapy, Nerve Degeneration physiopathology, Neurons drug effects, Neuroprotective Agents metabolism, Neuroprotective Agents pharmacology, Peptide Fragments antagonists & inhibitors, Peptide Fragments drug effects, Peptide Fragments metabolism, Peptide Fragments pharmacology, Peptide Fragments toxicity, Prion Diseases drug therapy, Prion Diseases physiopathology, Prions antagonists & inhibitors, Prions drug effects, Prions toxicity, Proteins pharmacology, Rats, Rats, Wistar, Signal Transduction drug effects, Signal Transduction physiology, Apoptosis physiology, Nerve Degeneration metabolism, Neurons metabolism, Prion Diseases metabolism, Prions metabolism, Proteins metabolism
- Abstract
We recently demonstrated that a soluble oligomeric prion peptide, the putative 118-135 transmembrane domain of prion protein (PrP), exhibited membrane fusogenic properties and induced apoptotic cell death both in vitro and in vivo. A recently discovered rescue factor humanin (HN) was shown to protect neuronal cells from various insults involved in human neurodegenerative diseases. We thus addressed the question of whether HN might modulate the apoptosis induced by the soluble PrP(118-135) fragment. We found that the incubation of rat cortical neurons with 10 microM HN prevented soluble PrP(118-135) fragment-induced cell death concomitantly with inhibition of apoptotic events. An HN variant, termed HNG, exhibited a 500-fold increase in the protective activity in cortical neurons, whereas the HNA variant displayed no protective effect. The effects of HN and HNG peptides did not require a preincubation with the PrP(118-135) fragment, strongly suggesting that these peptides rescue cells independently of a direct interaction with the prion peptide. By contrast, and in agreement with a previous study, HN had no effect on the fibrillar PrP(106-126) peptide-induced cell death. This protective effect for neurons from PrP(118-135)-induced cell death strongly suggests that PrP(118-135) and PrP(106-126) peptides may trigger different pathways leading to neuronal apoptosis.
- Published
- 2004
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43. Histopathological alterations and functional brain deficits after transient hypoxia in the newborn rat pup: a long term follow-up.
- Author
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Grojean S, Schroeder H, Pourié G, Charriaut-Marlangue C, Koziel V, Desor D, Vert P, and Daval JL
- Subjects
- Animals, Animals, Newborn, Brain metabolism, Cell Count methods, Follow-Up Studies, Hypoxia, Brain metabolism, Maze Learning physiology, Motor Activity physiology, Rats, Rats, Sprague-Dawley, Time Factors, Brain pathology, Brain physiopathology, Hypoxia, Brain pathology, Hypoxia, Brain physiopathology
- Abstract
To assess temporal brain deficits consecutive to severe birth hypoxia, newborn rats were exposed for 20 min to 100% N2. This treatment induced a long-term growth retardation and a delayed, but only transient, neuronal loss (approximately 25%) in the CA1 hippocampus and parietal cortex, starting from 3 days and peaking at 6 days post-hypoxia. The expression profiles of various apoptosis-regulating proteins (including Bcl-2, Bax, p53 and caspase-3) were well correlated to the alterations of nuclear morphology depicted by 4,6-diamidino-2-phenylindole (DAPI). Whereas they confirmed a gradual histological recovery, specific DNA fragmentation patterns suggested that birth hypoxia may transiently reactivate the developmental programme of neuronal elimination. Although they successfully achieved various behavioral tests such as the righting reflex, negative geotaxis, locomotor coordination, and the eight-arm maze tasks, both developing and adult hypoxic rats were repeatedly slower than controls, suggesting that birth hypoxia is associated to moderate but persistent impairments of functional capacities.
- Published
- 2003
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44. Apoptotic neuronal cell death induced by the non-fibrillar amyloid-beta peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation.
- Author
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Sponne I, Fifre A, Drouet B, Klein C, Koziel V, Pinçon-Raymond M, Olivier JL, Chambaz J, and Pillot T
- Subjects
- Animals, Caspases metabolism, Cerebral Cortex embryology, Cytoskeleton drug effects, Embryo, Mammalian, Enzyme Activation, Enzyme Inhibitors pharmacology, Neurons drug effects, Neurons physiology, Rats, Rats, Wistar, Amyloid beta-Peptides pharmacology, Apoptosis physiology, Cerebral Cortex cytology, Cytoskeleton ultrastructure, Neurons cytology, Peptide Fragments pharmacology, Reactive Oxygen Species metabolism
- Abstract
In the present study, we have determined the nature and the kinetics of the cellular events triggered by the exposure of cells to non-fibrillar amyloid-beta peptide (A beta). When cortical neurons were treated with low concentrations of soluble A beta (1-40), an early reactive oxygen species (ROS)-dependent cytoskeleton disruption precedes caspase activation. Indeed, caspase activation and neuronal cell death were prevented by the microtubule-stabilizing drug taxol. A perturbation of the microtubule network was noticeable after being exposed to A beta for 1 h, as revealed by electron microscopy and immunocytochemistry. Microtubule disruption and neuronal cell death induced by A beta were inhibited in the presence of antioxidant molecules, such as probucol. These data highlight the critical role of ROS production in A beta-mediated cytoskeleton disruption and neuronal cell death. Finally, using FRAP (fluorescence recovery after photo bleaching) analysis, we observed a time-dependent biphasic modification of plasma membrane fluidity, as early as microtubule disorganization. Interestingly, molecules that inhibited neurotubule perturbation and cell death did not affect the membrane destabilizing properties of A beta, suggesting that the lipid phase of the plasma membrane might represent the earliest target for A beta. Altogether our results convey the idea that upon interaction with the plasma membrane, the non-fibrillar A beta induces a rapid ROS-dependent disorganization of the cytoskeleton, which results in apoptosis.
- Published
- 2003
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45. Bilirubin exerts additional toxic effects in hypoxic cultured neurons from the developing rat brain by the recruitment of glutamate neurotoxicity.
- Author
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Grojean S, Lievre V, Koziel V, Vert P, and Daval JL
- Subjects
- Animals, Brain cytology, Cells, Cultured, Excitatory Amino Acid Antagonists pharmacology, Female, Rats, Rats, Sprague-Dawley, Receptors, Glutamate drug effects, Bilirubin toxicity, Brain drug effects, Cell Hypoxia, Glutamic Acid toxicity
- Abstract
Both hypoxia and bilirubin are common risk factors in newborns, which may act synergistically to produce anatomical and functional disturbances of the CNS. Using primary cultures of neurons from the fetal rat brain, it was recently reported that neuronal apoptosis accounts for the deleterious consequences of these two insults. To investigate the influence of hypoxia, bilirubin, or their combination on the outcome of neuronal cells of the immature brain, and delineate cellular mechanisms involved, 6-d-old cultured neurons were submitted to either hypoxia (6 h), unconjugated bilirubin (0.5 microM), or to combined conditions. Within 96 h, cell viability was reduced by 22.7% and 24.5% by hypoxia and bilirubin, respectively, whereas combined treatments decreased vital score by 34%. Nuclear morphology revealed 13.4% of apoptotic cells after hypoxia, 16.2% after bilirubin, and 22.6% after both treatments. Bilirubin action was specifically blocked by the glutamate receptor antagonist MK-801, which was without effect on the consequences of hypoxia. Temporal changes in [(3)H]leucine incorporation rates as well as beneficial effects of cycloheximide reflected a programmed phenomenon dependent upon synthesis of selective proteins. The presence of bilirubin reduced hypoxia-induced alterations of cell energy metabolism, as reflected by 2-D-[(3)H]deoxyglucose incorporation, raising the question of free radical scavenging. Measurements of intracellular radical generation, however, failed to confirm the antioxidant role of bilirubin. Taken together, our data suggest that low levels of bilirubin may enhance hypoxia effects in immature neurons by facilitating glutamate-mediated apoptosis through the activation of N:-methyl-D-aspartate receptors.
- Published
- 2001
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46. Toxic effects of apomorphine on rat cultured neurons and glial C6 cells, and protection with antioxidants.
- Author
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dos Santos El-Bachá R, Daval J, Koziel V, Netter P, and Minn A
- Subjects
- Animals, Cell Survival drug effects, Cells, Cultured, DNA drug effects, DNA metabolism, DNA Damage, Dopamine Agonists toxicity, Drug Interactions, Electrophoresis, Agar Gel, Neuroglia ultrastructure, Neurons ultrastructure, Oxidation-Reduction drug effects, Proteins drug effects, Proteins metabolism, Rats, Antioxidants pharmacology, Apomorphine toxicity, Neuroglia drug effects, Neurons drug effects, Protective Agents pharmacology
- Abstract
Many catechol derivatives are currently used as drugs, even if they produce reactive oxygen species that may cause tissue damage. Among them, apomorphine, a potent dopamine agonist, displays efficient anti-parkinsonian properties, but the consequences of its oxidant and toxic properties have been poorly investigated on in vitro models. In the present work, we investigated apomorphine cytotoxicity by incubating cultures of rat glioma C6 cells and primary cultures of neurons with different concentrations of the drug. Apomorphine-promoted cell death was proportional to its concentration and was time-dependent. The ED(50) of apomorphine on C6 cell death after 48 hr was about 200 microM. The cytotoxic effects induced by apomorphine were correlated to its autoxidation, which leads to the formation of reactive oxygen species, semiquinones, quinones, and a melanin-like pigment. C6 cells that underwent treatment with 400 microM apomorphine for 6 hr displayed features of necrosis, including loss of membrane integrity, degeneration of mitochondria, and DNA fragmentation. Thiols, such as cysteine, N-acetyl-L-cysteine, and glutathione, significantly protected cultured neurons and C6 cells against apomorphine-induced cytotoxicity. Thiols also inhibited apomorphine autoxidation. These data strongly suggest that apomorphine cytotoxicity towards neurons and C6 cells results from an intracellular oxidative stress.
- Published
- 2001
- Full Text
- View/download PDF
47. Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons.
- Author
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Grojean S, Koziel V, Vert P, and Daval JL
- Subjects
- Animals, Apoptosis physiology, Caspases metabolism, Cells, Cultured, Cycloheximide pharmacology, Cysteine Proteinase Inhibitors pharmacology, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Antagonists pharmacology, Female, Fluorescent Dyes pharmacokinetics, Indoles pharmacokinetics, Male, Neurons enzymology, Oligopeptides pharmacology, Pregnancy, Prosencephalon cytology, Prosencephalon embryology, Protein Kinase C metabolism, Protein Synthesis Inhibitors pharmacology, Quinoxalines pharmacology, Rats, Rats, Sprague-Dawley, Thymidine metabolism, Thymidine pharmacology, Tritium, Apoptosis drug effects, Bilirubin toxicity, Neurons cytology, Neurons drug effects, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
Increased amounts of bilirubin, the end product of heme degradation, are known to be detrimental to the central nervous system, especially in preterm newborns. In an attempt to delineate the cellular mechanisms by which unconjugated bilirubin exerts its toxic effects on neuronal cells in the developing brain, bilirubin (0.25-5 microM) was added to the extracellular medium of 6-day-old primary cultured neurons from the embryonic rat forebrain, and cell alterations were studied over the ensuing 96 h. Bilirubin decreased cell viability dose dependently with an ED(50) around 1 microM. At the dose of 0.5 microM, it triggered delayed cell death that affected 24% of the neurons. Nuclear incorporation of the fluorescent dye DAPI (4,6-diamidino-2-phenylindole) depicted the presence of apoptosis (16%). Apoptosis features were confirmed by DNA fragmentation reflected by a progressive loss of [(3)H]thymidine and sequential changes in macromolecular synthesis, as shown by the time course of [(3)H]leucine incorporation, as well as by the beneficial effects of cycloheximide and caspase inhibitors. In parallel, treatments with glutamate receptor antagonists showed that MK-801, but not NBQX, protected neurons against bilirubin neurotoxicity, suggesting a role for NMDA receptors in bilirubin effects. Coupled with previous work about glutamate toxicity in the same culture model, these data support the hypothesis that low levels of free bilirubin may promote programmed neuronal death corresponding to an apoptotic process which involves caspase activation and requires the participation of NMDA receptors, along with bilirubin-induced inhibition of protein kinase C activity., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
- View/download PDF
48. Effects of hypothermia on hypoxia-induced apoptosis in cultured neurons from developing rat forebrain: comparison with preconditioning.
- Author
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Bossenmeyer-Pourié C, Koziel V, and Daval JL
- Subjects
- Animals, Cells, Cultured, DNA biosynthesis, Female, Immunohistochemistry, Prosencephalon embryology, Prosencephalon metabolism, Protein Biosynthesis, Rats, Rats, Sprague-Dawley, Apoptosis, Hypothermia, Hypoxia pathology, Ischemic Preconditioning, Prosencephalon pathology
- Abstract
In neuronal cultures from the forebrain of 14-d-old rat embryos, transient hypoxia (95% N2/5% CO2, 37 degrees C) for 6 h has been shown to trigger delayed apoptotic death through sequential changes in protein synthesis, whereas preconditioning by a brief episode of hypoxia can rescue neurons. Because hypothermia has been reported to be neuroprotective, the present study was designed to test the influence of reduced temperature on the consequences of lethal hypoxia in our culture model, and cellular mechanisms involved were compared with those underlying preconditioning effects. After 6 d in vitro, cultures were subjected to hypoxia for 6 h. They were either placed at 32 degrees C concomitantly with hypoxia for 6 h or preconditioned the day before by a 1-h episode of hypoxia. The hypoxic insult decreased cell viability by 38% at 96 h after reoxygenation, and 23% of the neurons showed morphologic features of apoptosis. Both hypothermia and preconditioning prevented neuronal death and reduced apoptosis. Preconditioning led to time-dependent changes in leucine incorporation, with persistent overexpression of the survival proteins Bcl-2 and heat-shock protein 70. It also increased thymidine incorporation, in line with induction of the cofactor for DNA polymerase, proliferating cell nuclear antigen. Hypothermia reduced basal apoptosis and necrosis, but did not affect thymidine incorporation, and abolished hypoxia-associated protein synthesis. Therefore, both treatments were protective against neuronal injury consecutive to hypoxia in developing brain neurons in vitro. Whereas preconditioning activated a program that stimulated the expression of anti-apoptotic gene products and regulatory components of the cell cycle, hypothermia did not trigger active processes, but depressed cell activity, which in turn may impair the apoptotic phenomenon.
- Published
- 2000
- Full Text
- View/download PDF
49. Involvement of caspase-1 proteases in hypoxic brain injury. effects of their inhibitors in developing neurons.
- Author
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Bossenmeyer-Pourié C, Koziel V, and Daval JL
- Subjects
- Animals, Blotting, Western, Brain embryology, Caspase 1 metabolism, Cell Nucleus ultrastructure, Cell Survival, Cells, Cultured, Cellular Senescence physiology, Cysteine Proteinase Inhibitors pharmacology, Immunohistochemistry, Neurons enzymology, Neurons physiology, Neurons ultrastructure, Peptide Hydrolases metabolism, Protease Inhibitors pharmacology, Rats, Rats, Sprague-Dawley, Brain enzymology, Brain pathology, Caspase 1 physiology, Hypoxia enzymology, Hypoxia pathology
- Abstract
To further explore the contribution of caspase-1/interleukin-1beta-convening enzyme in the consequences of hypoxia in developing brain neurons, its temporal expression profile was analysed by immunohistochemistry and western blotting in cultured neurons from the embryonic rat forebrain subjected to a hypoxic stress (95% N2/5% CO2 for 6 h), and proteolytic activity of caspase-1 was monitored as a function of time by measuring the degradation of a selective colorimetric substrate (N-acetyl-Tyr-Val-Ala-Asp-p-nitroanilide). In addition, the influence of pre- and posthypoxic treatments by caspase-1 inhibitors (N-acetyl-Tyr-Val-Ala-Asp-aldehyde and N-acetyl-Tyr-Val-Ala-Asp-chloromethylketone) was tested on cell outcome. Hypoxia led to delayed apoptotic neuronal death, with an elevation of the expression of both pro-caspase-1 and caspase-1 active cleavage product (ICE p20) for up to 96 h after cell reoxygenation. As reflected by cleavage of the specific substrate, caspase-1 activity progressively increased between 24 h and 96 h posthypoxia, and was blocked by inhibitors in a dose-dependent fashion. The inhibitory compounds, including when given 24 h after hypoxia, prevented neuronal death, reduced apoptosis hallmarks and also increased the number of mitotic neurons, suggesting they might promote neurogenesis. Similar observations were made when neurons were exposed to a sublethal hypoxia (i.e. 3 h). These data emphasize the participation of caspase-1 in neuronal injury consecutive to oxygen deprivation, and provide new insight into the possible cellular mechanisms by which caspase inhibitors may protect developing brain neurons.
- Published
- 2000
- Full Text
- View/download PDF
50. CPP32/CASPASE-3-like proteases in hypoxia-induced apoptosis in developing brain neurons.
- Author
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Bossenmeyer-Pourié C, Koziel V, and Daval JL
- Subjects
- Animals, Blotting, Western, Caspase 3, Cell Hypoxia, Cell Survival, Cells, Cultured, Cysteine Proteinase Inhibitors pharmacology, DNA Repair, Female, Oligopeptides metabolism, Oligopeptides pharmacology, Poly(ADP-ribose) Polymerases metabolism, Rats, Rats, Sprague-Dawley, Apoptosis, Brain enzymology, Caspases metabolism, Enzyme Precursors metabolism, Neurons enzymology
- Abstract
Since caspase members have been identified as effectors of apoptosis, the role of CPP32/caspase-3 was further explored in cultured neurons from the embryonic rat forebrain submitted to a 6-h hypoxia which has previously been shown to induce apoptotic death within four days after reoxygenation, whereas a shorter aggression (i.e., for 3 h) leads by the same time to an increased number of living neurons, suggesting that sublethal hypoxia may promote neurogenesis. Neuronal expression of the active cleavage product of CPP32 (CPP32 p20) increased specifically after hypoxia for 6 h to finally reach 985% over control normoxic values at 96 h post-insult, while a 3-h hypoxia triggered the inducible stress protein HSP70 that has been shown to inhibit caspase-3. Proteolytic activity of caspase-3 was progressively stimulated by lethal hypoxia, as reflected by the degradation of two selective substrates, including poly (ADP-ribose) polymerase (PARP). Caspase-3 activity was blocked specifically and dose-dependently by the peptide inhibitor, DEVD-CHO, that reduced the number of apoptotic cells and prevented the hypoxia-induced decrease in cell viability, including when given 24 h post-insult. Interestingly, in these conditions, the inhibitory compounds enhanced the number of mitotic neurons. These data emphasize the critical role of caspase-3 in neuronal injury consecutive to hypoxia. Whereas caspase inhibitors may provide benefit over a broad therapeutic window, they might allow developing neurons to complete their cell cycle initiated in response to stress, as it is the case for sublethal hypoxia.
- Published
- 1999
- Full Text
- View/download PDF
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