Publications by authors named "Laurent Bezin"

34 Publications

Relation between coffee consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy.

Epilepsia 2021 Mar 14;62(3):765-777. Epub 2021 Feb 14.

Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and University of Lyon, Lyon, France.

Objective: Caffeine is an antagonist of the adenosine pathway, which is involved in regulation of breathing. Extracellular concentrations of adenosine are increased in the immediate aftermath of a seizure. Seizure-related overstimulation of adenosine receptors might promote peri-ictal apnea. However, the relation between caffeine consumption and risk of seizure-related respiratory dysfunction in patients with drug-resistant focal epilepsy remains unknown.

Methods: We performed a cross-sectional analysis of data collected in patients included in the SAVE study in Lyon's epilepsy monitoring unit at the Adult Epilepsy Department of the Lyon University Hospital between February 2016 and October 2018. The video-electroencephalographic recordings of 156 patients with drug-resistant focal epilepsy included in the study were reviewed to identify those with ≥1 focal seizure (FS), valid pulse oximetry (SpO ) measurement, and information about usual coffee consumption. This latter was collected at inclusion using a standardized self-questionnaire and further classified into four groups: none, rare (≤3 cups/week), moderate (4 cups/week to 3 cups/day), and high (≥4 cups/day). Peri-ictal hypoxemia (PIH) was defined as SpO < 90% for at least 5 s occurring during the ictal period, the post-ictal period, or both.

Results: Ninety patients fulfilled inclusion criteria, and 323 seizures were analyzed. Both the level of usual coffee consumption (p = .033) and the level of antiepileptic drug withdrawal (p = .004) were independent risk factors for occurrence of PIH. In comparison with FS in patients with no coffee consumption, risk of PIH was four times lower in FS in patients with moderate consumption (odds ratio [OR] = .25, 95% confidence interval [CI] = .07-.91, p = .036) and six times lower in FS in patients with high coffee consumption (OR = .16, 95% CI = .04-.66, p = .011). However, when PIH occurred, its duration was longer in patients with moderate or high consumption than in those with no coffee consumption (p = .042).

Significance: Coffee consumption may be a protective factor for seizure-related respiratory dysfunction, with a dose-dependent effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16837DOI Listing
March 2021

Mitigation of Expression of Virulence Genes in Internalized in the Free-Living Amoeba C2c Maky.

Pathogens 2020 Jun 5;9(6). Epub 2020 Jun 5.

R&D Department, Amoéba, 69680 Chassieu, France.

is a human pathogen responsible for a severe form of pneumonia named Legionnaire disease. Its natural habitat is aquatic environments, being in a free state or intracellular parasites of free-living amoebae, such as . This pathogen is able to replicate within some amoebae. C2c Maky, a non-pathogenic amoeba, was previously demonstrated to resist to and even to be able to eliminate the strains Philadelphia, Lens, and Paris. Here, we studied the induction of seven virulence genes of three strains (Paris, Philadelphia, and Lens) within C2c Maky in comparison within and with the gene expression level of strains alone used as controls. We defined a gene expression-based virulence index to compare easily and without bias the transcript levels in different conditions and demonstrated that C2c Maky did not increase the virulence of strains in contrast to . These results confirmed the non-permissiveness of C2c Maky toward strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pathogens9060447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350332PMC
June 2020

Transient hypoxemia induced by cortical electrical stimulation: A mapping study in 75 patients.

Neurology 2020 06 5;94(22):e2323-e2336. Epub 2020 May 5.

From the Departments of Functional Neurology and Epileptology (M.L., J.J., S.R.) and Functional Neurosurgery (M.G.), Hospices Civils de Lyon and University of Lyon, France; Department of Clinical Neurosciences (P.R.), Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland; INSERM U1028/CNRS UMR 5292 (B.C., J.J., R.B., M.G., L.M., L.B., S.R.), Lyon's Neuroscience Research Center; Neurology Department (L.M.), University Hospital, Saint-Etienne; and Epilepsy Institute (L.B., S.R.), Lyon, France.

Objective: To identify which cortical regions are associated with direct electrical stimulation (DES)-induced alteration of breathing significant enough to impair pulse oximetry (SpO).

Methods: Evolution of SpO after 1,352 DES was analyzed in 75 patients with refractory focal epilepsy who underwent stereo-EEG recordings. For each DES, we assessed the change in SpO from 30 seconds prior to DES onset to 120 seconds following the end of the DES. The primary outcome was occurrence of stimulation-induced transient hypoxemia as defined by decrease of SpO ≥5% within 60 seconds after stimulation onset as compared to pre-DES SpO or SpO nadir <90% during at least 5 seconds. Localization of the stimulated contacts was defined according to MarsAtlas brain parcellation and Freesurfer segmentation.

Results: A stimulation-induced transient hypoxemia was observed after 16 DES (1.2%) in 10 patients (13%), including 6 in whom SpO nadir was <90%. Among these 16 DES, 7 (44%) were localized within the perisylvian cortex. After correction for individual effects and the varying number of DES contributed by each person, significant decrease of SpO was significantly associated with the localization of DES ( = 0.019).

Conclusion: Though rare, a significant decrease of SpO could be elicited by cortical direct electrical stimulation outside the temporo-limbic structures, most commonly after stimulation of the perisylvian cortex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009497DOI Listing
June 2020

Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta-induced pathology.

Neurobiol Aging 2019 09 13;81:88-101. Epub 2019 May 13.

Laboratory of Neural Plasticity, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark; Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address:

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the irreversible neuronal loss and memory impairment, and current treatments are merely symptomatic. Erythropoietin (EPO) has been shown to possess neurotrophic, neuroprotective, anti-inflammatory, and memory-enhancing effects, which could be therapeutically beneficial in the different aspects of AD. However, the hematopoietic effect of EPO has hampered its potential as a neuroprotective and procognitive agent. In this study, we characterized a novel small peptide, NL100, derived from a conserved C-helix region of EPO. NL100 was shown to bind to the EPO receptor, induce neuritogenesis, and protect hippocampal neurons from oxidative- and Aβ-induced neurodegeneration in vitro. Importantly, long-term NL100 treatment did not induce hematopoiesis, overcoming this challenge associated with EPO. Memory-enhancing effects were demonstrated after NL100 treatment in social recognition test for short-term memory, in both healthy rats and rats challenged centrally with Aβ peptide, and in the Morris water maze test for spatial memory. Moreover, NL100 was shown to reverse Aβ-induced hippocampal degeneration and gliosis as well as pilocarpine-induced suppression of long-term potentiation in rats. In conclusion, NL100 is a novel EPO-derived nonhematopoietic peptide with neuroprotective and memory-enhancing effects and could therefore be a potential candidate for the development of new treatments for neurodegenerative disorders and dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.05.003DOI Listing
September 2019

Hypoxemia following generalized convulsive seizures: Risk factors and effect of oxygen therapy.

Neurology 2019 01 19;92(3):e183-e193. Epub 2018 Dec 19.

From the Department of Functional Neurology and Epileptology (S.R., B.M.A., V.A.), Hospices Civils de Lyon and University of Lyon; Lyon's Neuroscience Research Center (S.R., B.M.A., V.A., L.B., P.R.), INSERM U1028/CNRS UMR 5292, France; Hospital of Clinics of Ribeirão Preto (V.A.), University of São Paulo, Brazil; Department of Neurology (J.C., L.V.), University Hospital of Toulouse; Neurology Department (L.M.), University Hospital of Nancy; Clinical Neurophysiology and Epileptology Department (F.B.), Timone Hospital, Marseille; Department of Clinical Neurophysiology (P.D.), Lille University Medical Center, EA 1046, University of Lille2; Department of Neurology (E.H.), University Hospital of Strasbourg; Department of Neurology (V.M.), Hôpital Pellegrin, Bordeaux; Epilepsy Unit, Department of Neurosurgery (F.C.), Centre Hospitalier Sainte-Anne, University Paris Descartes; La Teppe Epilepsy Center (D.T.), Tain l'Hermitage,; Epilepsy Unit (A.C.), Montpellier; Department of Neurology (A.B.), University Hospital of Rennes; Epileptology Unit (V.N.), Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière and Brain and Spine Institute (ICM; INSERM UMRS1127, CNRS UMR7225, UPMC University Paris 06); Department of Neurology (P.K.), Grenoble-Alpes University Hospital, GIN, INSERM U1216, and Grenoble Alpes University; Department of Clinical Neurophysiology (B.D.T.), INSERM U930, University Hospital of Tours; Department of Neurology (P.T.), University Hospital of Nice; Department of Neurology (S.R.), University Hospital of Clermont-Ferrand, France; Department of Clinical Neurosciences (S.R., P.R.), Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland; and Epilepsy Institute (E.H., L.B., P.R.), Lyon, France.

Objective: To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS).

Methods: We reviewed the video-EEG recordings of 1,006 patients with drug-resistant focal epilepsy included in the REPOMSE study to identify those with ≥1 GCS and pulse oximetry (SpO) measurement. Factors determining recovery of SpO ≥ 90% were investigated using Cox proportional hazards models. Association between SpO nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures.

Results: A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 GCS (86%). Rate of GCS with SpO <70% dropped from 40% to 21% when oxygen was administered early ( = 0.046). Early recovery of SpO ≥90% was associated with early administration of oxygen ( = 0.004), absence of postictal generalized EEG suppression (PGES) ( = 0.014), and extratemporal lobe epilepsy ( = 0.001). Lack of early administration of O ( = 0.003), occurrence of PGES ( = 0.018), and occurrence of ictal hypoxemia during the focal phase ( = 0.022) were associated with lower SpO nadir.

Conclusion: Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000006777DOI Listing
January 2019

Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome.

Elife 2017 10 31;6. Epub 2017 Oct 31.

Aix Marseille Univ, INSERM, INMED, Marseille, France.

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder that presents with hypotonia and respiratory distress in neonates. The -deficient mouse is the only model that reproduces the respiratory phenotype of PWS (central apnea and blunted response to respiratory challenges). Here, we report that deletion disturbs the migration of serotonin (5-HT) neuronal precursors, leading to altered global serotonergic neuroarchitecture and increased spontaneous firing of 5-HT neurons. We show an increased expression and activity of 5-HT Transporter (SERT/Slc6a4) in 5-HT neurons leading to an increase of 5-HT uptake. In -KO pups, the genetic deletion of or treatment with Fluoxetine, a 5-HT reuptake inhibitor, restored normal breathing. Unexpectedly, Fluoxetine administration was associated with respiratory side effects in wild-type animals. Overall, our results demonstrate that an increase of SERT activity is sufficient to cause the apneas in KO pups, and that fluoxetine may offer therapeutic benefits to PWS patients with respiratory complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.32640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711373PMC
October 2017

Cognitive Deficits and Inflammatory Response Resulting from Mild-to-Moderate Traumatic Brain Injury in Rats Are Exacerbated by Repeated Pre-Exposure to an Innate Stress Stimulus.

J Neurotrauma 2017 04 13;34(8):1645-1657. Epub 2017 Jan 13.

2 Université Claude Bernard Lyon 1 , Bron, France .

Traumatic brain injury (TBI) is common in both military and civilian populations, and often results in neurobehavioral sequelae that impair quality of life in both patients and their families. Although individuals who are chronically exposed to stress are more likely to experience TBI, it is still unknown whether pre-injury stress influences the outcome after TBI. The present study tested whether behavioral and cognitive long-term outcome after TBI in rats is affected by prior exposure to an innate stress stimulus. Young adult male Sprague-Dawley rats were exposed to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) or to water (WAT); exposure was repeated eight times at irregular intervals over a 2-week period. Rats were subsequently subjected to either mild-to-moderate bilateral brain injury (lateral fluid percussion [LFP]) or sham surgery (Sham). Four experimental groups were studied: Sham-WAT, Sham-TMT, LFP-WAT and LFP-TMT. Compared with Sham-WAT rats, LFP-WAT rats exhibited transient locomotor hyperactivity without signs of anxiety, minor spatial learning acquisition and hippocampal long-term potentiation deficits, and lower baseline activity of the hypothalamic-pituitary-adrenal axis with slightly stronger reactivity to restraint stress. Exposure to TMT had only negligible effects on Sham rats, whereas it exacerbated all deficits in LFP rats except for locomotor hyperactivity. Early brain inflammatory response (8 h post-trauma) was aggravated in rats pre-exposed to TMT, suggesting that increased brain inflammation may sustain functional deficits in these rats. Hence, these data suggest that pre-exposure to stressful conditions can aggravate long-term deficits induced by TBI, leading to severe stress response deficits, possibly due to dysregulated inflammatory response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/neu.2016.4741DOI Listing
April 2017

Altered hypermetabolic response to cortical spreading depolarizations after traumatic brain injury in rats.

J Cereb Blood Flow Metab 2017 May 1;37(5):1670-1686. Epub 2016 Jan 1.

1 Inserm U1028, CNRS UMR 5292, Lyon Neuroscience Research Center, Team TIGER, Lyon, France.

Spreading depolarizations are waves of near-complete breakdown of neuronal transmembrane ion gradients, free energy starving, and mass depolarization. Spreading depolarizations in electrically inactive tissue are associated with poor outcome in patients with traumatic brain injury. Here, we studied changes in regional cerebral blood flow and brain oxygen (PbtO), glucose ([Glc]b), and lactate ([Lac]b) concentrations in rats, using minimally invasive real-time sensors. Rats underwent either spreading depolarizations chemically triggered by KCl in naïve cortex in absence of traumatic brain injury or spontaneous spreading depolarizations in the traumatic penumbra after traumatic brain injury, or a cluster of spreading depolarizations triggered chemically by KCl in a remote window from which spreading depolarizations invaded penumbral tissue. Spreading depolarizations in noninjured cortex induced a hypermetabolic response characterized by a decline in [Glc]b and monophasic increases in regional cerebral blood flow, PbtO, and [Lac]b, indicating transient hyperglycolysis. Following traumatic brain injury, spontaneous spreading depolarizations occurred, causing further decline in [Glc]b and reducing the increase in regional cerebral blood flow and biphasic responses of PbtO and [Lac]b, followed by prolonged decline. Recovery of PbtO and [Lac]b was significantly delayed in traumatized animals. Prespreading depolarization [Glc]b levels determined the metabolic response to clusters. The results suggest a compromised hypermetabolic response to spreading depolarizations and slower return to physiological conditions following traumatic brain injury-induced spreading depolarizations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0271678X16657571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435292PMC
May 2017

WNT4 mediates the autocrine effects of growth hormone in mammary carcinoma cells.

Endocr Relat Cancer 2016 07 20;23(7):571-85. Epub 2016 Jun 20.

Centre de Recherche en Cancérologie de LyonUMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, France

The expression of Wingless and Int-related protein (Wnt) ligands is aberrantly high in human breast cancer. We report here that WNT4 is significantly upregulated at the mRNA and protein level in mammary carcinoma cells expressing autocrine human growth hormone (hGH). Depletion of WNT4 using small interfering (si) RNA markedly decreased the rate of human breast cancer cell proliferation induced by autocrine hGH. Forced expression of WNT4 in the nonmalignant human mammary epithelial cell line MCF-12A stimulated cell proliferation in low and normal serum conditions, enhanced cell survival and promoted anchorage-independent growth and colony formation in soft agar. The effects of sustained production of WNT4 were concomitant with upregulation of proliferative markers (c-Myc, Cyclin D1), the survival marker BCL-XL, the putative WNT4 receptor FZD6 and activation of ERK1 and STAT3. Forced expression of WNT4 resulted in phenotypic conversion of MCF-12A cells, such that they exhibited the molecular and morphological characteristics of mesenchymal cells with increased cell motility. WNT4 production resulted in increased mesenchymal and cytoskeletal remodeling markers, promoted actin cytoskeleton reorganization and led to dissolution of cell-cell contacts. In xenograft studies, tumors with autocrine hGH expressed higher levels of WNT4 and FZD6 when compared with control tumors. In addition, Oncomine data indicated that WNT4 expression is increased in neoplastic compared with normal human breast tissue. Accordingly, immunohistochemical detection of WNT4 in human breast cancer biopsies revealed higher expression in tumor tissue vs normal breast epithelium. WNT4 is thus an autocrine hGH-regulated gene involved in the growth and development of the tumorigenic phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-15-0528DOI Listing
July 2016

Locus Coeruleus Dysfunction in Transgenic Rats with Low Brain Angiotensinogen.

CNS Neurosci Ther 2016 Mar 18;22(3):230-7. Epub 2016 Jan 18.

INSERM U1028, CNRS UMR5292, University Claude Bernard Lyon 1, Lyon Neuroscience Research Center, Team TIGER, Lyon, France.

Aims: Transgenic TGR(ASrAOGEN)680 (TGR) rats with specific downregulation of glial angiotensinogen (AOGEN) synthesis develop cardiovascular deficits, anxiety, altered response to stress, and depression. Here, we evaluated whether these deficits are associated with alteration of the integrity of the noradrenergic system originating from locus coeruleus (LC) neurons.

Methods: Adult TGR rats were compared to control Sprague Dawley rats in terms of the following: tissue levels of transcripts encoding noradrenergic markers, tissue tyrosine hydroxylase (TH) protein level, in vivo TH activity, density of TH-containing fibers, behavioral response to novelty, locomotor activity, and polysomnography.

Results: TH expression was increased in the LC of TGR rats compared to controls. In LC terminal fields, there was an increase in density of TH-containing fibers in TGR rats that was associated with an elevation of in vivo TH activity. TGR rats also displayed locomotor hyperactivity in response to novelty. Moreover, polysomnographic studies indicated that daily paradoxical sleep duration was increased in TGR rats and that the paradoxical sleep rebound triggered by total sleep deprivation was blunted in these rats.

Conclusions: Altogether, these results suggest that disruption of astroglial AOGEN synthesis leads to cardiovascular, cognitive, behavioral, and sleep disorders that might be partly due to LC dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cns.12488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492901PMC
March 2016

Neuronal loss as evidenced by automated quantification of neuronal density following moderate and severe traumatic brain injury in rats.

J Neurosci Res 2016 Jan 9;94(1):39-49. Epub 2015 Oct 9.

INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Team WAKING, Lyon, France.

Traumatic brain injury causes widespread neurological lesions that can be reproduced in animals with the lateral fluid percussion (LFP) model. The characterization of the pattern of neuronal death generated in this model remains unclear, involving both cortical and subcortical brain regions. Here, 7 days after moderate (3 atmospheres absolute [ATA]) or severe (3.8 ATA) LFP, we estimated neuronal loss by using immunohistochemistry together with a computer-assisted automated method for quantifying neuronal density in brain sections. Neuronal counts were performed ipsilateral to the impact, in the parietal cortex ventral to the site of percussion, in the temporal cortex, in the dorsal thalamus, and in the hippocampus. These results were compared with the counts observed at similar areas in sham animals. We found that neuronal density was severely decreased in the temporal cortex (-60%), in the dorsal thalamus (-63%), and in area CA3 of the hippocampus (-36%) of injured animals compared with controls but was not significantly modified in the cortices located immediately ventral to the impact. Total cellular density increased in brain structures displaying neuronal death, suggesting the presence of gliosis. The increase in the severity of LFP did not change the pattern of neuronal injury. This automated method simplified the study of neuronal loss following traumatic brain injury and allowed the identification of a pattern of neuronal loss that spreads from the dorsal thalamus to the temporal cortex, with the most severe lesions being in brain structures remote from the site of impact.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.23676DOI Listing
January 2016

Automated immunohistochemical method to quantify neuronal density in brain sections: application to neuronal loss after status epilepticus.

J Neurosci Methods 2014 Mar 23;225:32-41. Epub 2014 Jan 23.

Université de Lyon, Lyon, France; INSERM, Institut National de la Santé et de la Recherche Médicale, U1028, Lyon Neuroscience Research Center, Lyon, France; CNRS, Centre National de la Recherche Scientifique, UMR5292, Lyon Neuroscience Research Center, Lyon, France; Plate-forme technologique AniRA-Neurochem, Lyon F-69000, France. Electronic address:

Background: To study neurotoxic processes, it is necessary to quantify the number of neurons in a given brain structure and estimate neuronal loss. Neuronal densities can be estimated by immunohistochemical quantitation of a neuronal marker such as the protein NeuN. However, NeuN expression may vary, depending on certain pathophysiological conditions and bias such quantifications.

New Method: We have developed a simple automatic quantification of neuronal densities in brain sections stained with DAPI and antibody to NeuN. This method determines the number of DAPI-positive nuclei also positive for NeuN in at least two adjacent sections within a Z-stack of optical sections.

Results: We tested this method in animals with induced status epilepticus (SE) a state of intractable persistent seizure that produces extensive neuronal injury. We found that SE significantly reduced neuronal density in the piriform cortex, the amygdala, the dorsal thalamus, the CA3 area of the hippocampus, the dentate gyrus and the hilus, but not in the somatosensory cortex or the CA1 area. SE resulted in increases in the total density of cellular nuclei within these brain structures, suggesting gliosis.

Comparison With Existing Methods: This automated method was more accurate than simply estimating the overall NeuN fluorescence intensity in the brain section, and as accurate, but less time-consuming, than manual cell counts.

Conclusion: This method simplifies and accelerates the unbiased quantification of neuronal density. It can be easily applied to other models of brain injury and neurodegeneration, or used to screen the efficacy of neuroprotective treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneumeth.2014.01.009DOI Listing
March 2014

Stochastic loss of silencing of the imprinted Ndn/NDN allele, in a mouse model and humans with prader-willi syndrome, has functional consequences.

PLoS Genet 2013 5;9(9):e1003752. Epub 2013 Sep 5.

INSERM, Institut de Neurobiologie de la Méditerranée (INMED) U901, Marseille, France ; Aix-Marseille Université, INMED UMR901, Marseille, France.

Genomic imprinting is a process that causes genes to be expressed from one allele only according to parental origin, the other allele being silent. Diseases can arise when the normally active alleles are not expressed. In this context, low level of expression of the normally silent alleles has been considered as genetic noise although such expression has never been further studied. Prader-Willi Syndrome (PWS) is a neurodevelopmental disease involving imprinted genes, including NDN, which are only expressed from the paternally inherited allele, with the maternally inherited allele silent. We present the first in-depth study of the low expression of a normally silent imprinted allele, in pathological context. Using a variety of qualitative and quantitative approaches and comparing wild-type, heterozygous and homozygous mice deleted for Ndn, we show that, in absence of the paternal Ndn allele, the maternal Ndn allele is expressed at an extremely low level with a high degree of non-genetic heterogeneity. The level of this expression is sex-dependent and shows transgenerational epigenetic inheritance. In about 50% of mutant mice, this expression reduces birth lethality and severity of the breathing deficiency, correlated with a reduction in the loss of serotonergic neurons. In wild-type brains, the maternal Ndn allele is never expressed. However, using several mouse models, we reveal a competition between non-imprinted Ndn promoters which results in monoallelic (paternal or maternal) Ndn expression, suggesting that Ndn allelic exclusion occurs in the absence of imprinting regulation. Importantly, specific expression of the maternal NDN allele is also detected in post-mortem brain samples of PWS individuals. Our data reveal an unexpected epigenetic flexibility of PWS imprinted genes that could be exploited to reactivate the functional but dormant maternal alleles in PWS. Overall our results reveal high non-genetic heterogeneity between genetically identical individuals that might underlie the variability of the phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1003752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764186PMC
March 2014

Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats.

PLoS One 2013 14;8(1):e53888. Epub 2013 Jan 14.

Université de Lyon, Lyon, France.

Environmental enrichment of laboratory animals influences brain plasticity, stimulates neurogenesis, increases neurotrophic factor expression, and protects against the effects of brain insult. However, these positive effects are not constantly observed, probably because standardized procedures of environmental enrichment are lacking. Therefore, we engineered an enriched cage (the Marlau™ cage), which offers: (1) minimally stressful social interactions; (2) increased voluntary exercise; (3) multiple entertaining activities; (4) cognitive stimulation (maze exploration), and (5) novelty (maze configuration changed three times a week). The maze, which separates food pellet and water bottle compartments, guarantees cognitive stimulation for all animals. Compared to rats raised in groups in conventional cages, rats housed in Marlau™ cages exhibited increased cortical thickness, hippocampal neurogenesis and hippocampal levels of transcripts encoding various genes involved in tissue plasticity and remodeling. In addition, rats housed in Marlau™ cages exhibited better performances in learning and memory, decreased anxiety-associated behaviors, and better recovery of basal plasma corticosterone level after acute restraint stress. Marlau™ cages also insure inter-experiment reproducibility in spatial learning and brain gene expression assays. Finally, housing rats in Marlau™ cages after severe status epilepticus at weaning prevents the cognitive impairment observed in rats subjected to the same insult and then housed in conventional cages. By providing a standardized enriched environment for rodents during housing, the Marlau™ cage should facilitate the uniformity of environmental enrichment across laboratories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053888PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544705PMC
July 2013

Vitellogenin-like gene expression in freshwater amphipod Gammarus fossarum (Koch, 1835): functional characterization in females and potential for use as an endocrine disruption biomarker in males.

Ecotoxicology 2011 Aug 24;20(6):1286-99. Epub 2011 Jun 24.

Cemagref, UR MALY, 3 bis quai Chauveau, CP 220, 69336, Lyon, France.

The induction of vitellogenin (Vtg) synthesis is widely accepted as a biomarker of estrogenic exposure in male and juvenile fish. Vtg synthesis has emerged as an interesting endpoint to assess endocrine disruptor (ED) effects in crustaceans. However, studies reporting induction of Vtg in male crustaceans are lacking. This study investigated the expression of the Vtg gene in a freshwater amphipod, Gammarus fossarum, using calibrated real-time reverse transcription polymerase chain reaction (real-time RT PCR). First, we described the basal pattern of expression in healthy male and female organisms at different reproductive moult stages, in order to validate the function of this gene. Females expressed from 200 to 700 times more Vtg transcripts than males, depending on the female reproductive stage. Females displayed significant elevation of Vtg mRNA levels at the end of the inter-moult phase and at the beginning of the pre-moult phase. Second, male gammarids were exposed to the estrogenic compound nonylphenol (NP) (0.05, 0.5, 5 and 50 μg L(-1)) and to the anti-androgen cyproterone (1, 10, 100 and 1000 μg L(-1)) for 2, 4, 8 and 16 days. Both chemicals altered the pattern of interindividual variability of Vtg gene expression in males with strong induction in some individuals. Finally, the impact of urban wastewater treatment plants (WWTP) on male Vtg gene expression was assessed in organisms transplanted in the field during in situ bioassay campaigns in three different watersheds. Induction of the Vtg mRNA level was observed in males transplanted downstream from WWTP effluent discharge in two of the three study sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10646-011-0685-2DOI Listing
August 2011

Antibodies preventing the interaction of tissue-type plasminogen activator with N-methyl-D-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis.

Stroke 2011 Aug 16;42(8):2315-22. Epub 2011 Jun 16.

INSERM U919, Serine Proteases and Pathophysiology of the Neurovascular Unit; UMR-CNRS 6232 Ci-NAPs, Cyceron, Bd Becquerel, 14074 Caen, France.

Background And Purpose: Tissue-type plasminogen activator (tPA) is the only drug approved for the acute treatment of ischemic stroke but with two faces in the disease: beneficial fibrinolysis in the vasculature and damaging effects on the neurovascular unit and brain parenchyma. To improve this profile, we developed a novel strategy, relying on antibodies targeting the proneurotoxic effects of tPA.

Methods: After production and characterization of antibodies (αATD-NR1) that specifically prevent the interaction of tPA with the ATD-NR1 of N-methyl-d-aspartate receptors, we have evaluated their efficacy in a model of murine thromboembolic stroke with or without recombinant tPA-induced reperfusion, coupled to MRI, near-infrared fluorescence imaging, and behavior assessments.

Results: In vitro, αATD-NR1 prevented the proexcitotoxic effect of tPA without altering N-methyl-d-aspartate-induced neurotransmission. In vivo, after a single administration alone or with late recombinant tPA-induced thrombolysis, antibodies dramatically reduced brain injuries and blood-brain barrier leakage, thus improving long-term neurological outcome.

Conclusions: Our strategy limits ischemic damages and extends the therapeutic window of tPA-driven thrombolysis. Thus, the prospect of this immunotherapy is an extension of the range of treatable patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.110.606293DOI Listing
August 2011

Enriched housing reverses age-associated impairment of cognitive functions and tPA-dependent maturation of BDNF.

Neurobiol Learn Mem 2011 Sep 2;96(2):121-9. Epub 2011 Apr 2.

INSERM, INSERM U919, SP(2)U, Centre for Imaging-Neuroscience and Applications to Pathologies, GIP CYCERON, University of Caen Basse-Normandie (UCBN), F-14074 Caen Cedex, France.

Although tissue type plasminogen activator (tPA) and brain derived neurotrophic factor (BDNF) have been extensively described to influence brain outcomes in a number of disorders, their roles during physiological aging are poorly investigated. In the present study, we investigated whether maintenance of mice in different environmental conditions could influence age-associated changes in hippocampal tPA expression and BDNF maturation in relation with modifications of their cognitive performances. Our data indicate that maintenance in enriched housing led to a reversal of age-associated decrease in expression of hippocampal tPA. A subsequent increase in the level of mature BDNF and an improvement in emotional and spatial memories were observed. Taken together, these data suggest that the tPA-BDNF axis could play a critical role in the control of cognitive functions influenced both by the age and housing conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nlm.2011.03.004DOI Listing
September 2011

Functional occurrence of the interaction of tissue plasminogen activator with the NR1 Subunit of N-methyl-D-aspartate receptors during stroke.

Stroke 2010 Dec 21;41(12):2950-5. Epub 2010 Oct 21.

INSERM U919 serine proteases and pathophysiology of the neurovascular unit, UMR CNRS 6232 Cinaps, GIP Cyceron, Bd Becquerel, BP5229, 14074 Caen, France.

Background And Purpose: Despite its fibrinolytic effect, tissue-type plasminogen activator (tPA) displays deleterious effects in the brain, including proexcitotoxicity, that can reduce the overall benefit from thrombolysis during stroke. We have proposed that tPA potentiates excitotoxicity by interacting with and cleaving the aminoterminal end of the NR1 subunit of N-methyl-d-aspartate receptors, leading to an increased calcium influx, Erk1/2 activation, and neurotoxicity. Because this mechanism is debated, our aim was to demonstrate its in vivo occurrence and relevance. Because tPA is released under ischemic conditions, we hypothesized that if it indeed processes NR1, then the released fragment should reactivate the immune system in animals that had been immunized long before with recombinant aminoterminal end of the NR1. This effect should be exacerbated in ischemic animals thrombolysed with recombinant tPA.

Methods: At a time when specific antibodies could not be detected any longer, mice previously vaccinated with recombinant aminoterminal end of the NR1 were subjected to thromboembolic stroke induced by injecting thrombin in the middle cerebral artery alone or with intravenous thrombolysis.

Results: Stroke performed 1 year after active immunization induced the reappearance of antibodies against the aminoterminal end of the NR1 in the plasma, an effect significantly increased when ischemia was followed by recombinant tPA-induced reperfusion. Moreover, immunization preventing the interaction of tPA with aminoterminal end of the NR1 reduced ischemic brain damages and extended the therapeutic window of tPA-induced thrombolysis.

Conclusions: We demonstrate that the tPA-dependent interaction and cleavage of the NR1 subunit of N-methyl-d-aspartate receptors occurs in vivo after stroke and that this interaction is a relevant therapeutic target for stroke treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.110.592360DOI Listing
December 2010

Habitual physical activity and endothelial activation in sickle cell trait carriers.

Med Sci Sports Exerc 2010 Nov;42(11):1987-94

Center of Research and Innovation on Sports, University Claude Bernard of Lyon 1, University of Lyon, Lyon, France.

Purpose: It remains unclear whether habitual physical activity in sickle cell trait (SCT) carriers modulates the levels of resting and postexercise vascular adhesion and inflammatory molecules.

Methods: Plasma levels of pro-inflammatory (interleukin (IL)-4, IL-5, IL-8, sCD40L, and tumor necrosis factor α) and anti-inflammatory (IL-10) cytokines and adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), sP-selectin, or sE-selectin) were assessed at rest and in response to an incremental exercise to exhaustion in untrained (UT: no regular physical activity) and trained (T: soccer players, 8 h·wk minimum) SCT and control (CON) subjects (n = 8 per group; age = 23.5 ± 0.35 yr).

Results: sVCAM-1 levels were significantly higher in the UT-SCT group than that in T-SCT group (+43.5%) at rest, at the end, and at 1, 2, and 24 h after the end of the exercise. For the other molecules, no differences emerged among the groups at rest, but in response to exercise plasma, sICAM-1, sVCAM-1, sE-selectin, and sCD40L increased in all groups, and sP-selectin only increased in the UT group. All values that increased with the acute exercise returned to their respective baseline levels 1 h after the end of the exercise.

Conclusions: A physically active lifestyle in SCT carriers may decrease endothelial activation and may limit the risk for vascular adhesion events in the microcirculation of SCT subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1249/MSS.0b013e3181e054d6DOI Listing
November 2010

Dysregulation of ribosome biogenesis and translational capacity is associated with tumor progression of human breast cancer cells.

PLoS One 2009 Sep 25;4(9):e7147. Epub 2009 Sep 25.

Université de Lyon, Université Lyon 1, CNRS, UMR 5534, Centre Léon Bérard, Lyon, France.

Protein synthesis is a fundamental cell process and ribosomes - particularly through the ribosomal RNA that display ribozyme activity--are the main effectors of this process. Ribosome biogenesis is a very complex process involving transcriptional aswell as many post-transcriptional steps to produce functional ribosomes. It is now well demonstrated that ribosome production is enhanced in cancer cells and that ribosome biogenesis plays a crucial role in tumor progression. However, at present there is an important lack of data to determine whether the entire process of ribosome biogenesis and ribosome assembly is modified during tumor progression and what could be the potential impact on the dysregulation of translational control that is observed in cancer cells. In breast cancer cells displaying enhanced aggressivity, both in vitro and in vivo, we have analyzed the major steps of ribosome biogenesis and the translational capacity of the resulting ribosome. We show that increased tumorigenicity was associated with modifications of nucleolar morphology and profound quantitative and qualitative alterations in ribosomal biogenesis and function. Specifically cells with enhanced tumor aggressivity displayed increased synthesis of 45S pre-rRNA, with activation of an alternative preRNA synthetic pathway containing a 43S precursor and enhanced post-transcriptional methylation of specifc sites located in the 28S rRNA. While the global translational activity was not modified, IRES-initiated translation, notably that of p53 mRNA, was less efficient and the control of translational fidelity was importantly reduced in cells with increased aggressivity. These results suggest that acquisition of enhanced tumor aggressivity can be associated with profound qualitative alterations in ribosomal control, leading to reduced quality control of translation in cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744998PMC
September 2009

Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons.

Proc Natl Acad Sci U S A 2009 Jun 3;106(24):9848-53. Epub 2009 Jun 3.

University of Lyon, F-69003 Lyon, France.

Erythropoietin receptor (EpoR) binding mediates neuroprotection by endogenous Epo or by exogenous recombinant human (rh)Epo. The level of EpoR gene expression may determine tissue responsiveness to Epo. Thus, harnessing the neuroprotective power of Epo requires an understanding of the Epo-EpoR system and its regulation. We tested the hypothesis that neuronal expression of EpoR is required to achieve optimal neuroprotection by Epo. The ventral limbic region (VLR) in the rat brain was used because we determined that its neurons express minimal EpoR under basal conditions, and they are highly sensitive to excitotoxic damage, such as occurs with pilocarpine-induced status epilepticus (Pilo-SE). We report that (i) EpoR expression is significantly elevated in nearly all VLR neurons when rats are subjected to 3 moderate hypoxic exposures, with each separated by a 4-day interval; (ii) synergistic induction of EpoR expression is achieved in the dorsal hippocampus and neocortex by the combination of hypoxia and exposure to an enriched environment, with minimal increased expression by either treatment alone; and (iii) rhEpo administered after Pilo-SE cannot rescue neurons in the VLR, unless neuronal induction of EpoR is elicited by hypoxia before Pilo-SE. This study thus demonstrates using environmental manipulations in normal rodents, the strict requirement for induction of EpoR expression in brain neurons to achieve optimal neuroprotection. Our results indicate that regulation of EpoR gene expression may facilitate the neuroprotective potential of rhEpo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0901840106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701030PMC
June 2009

Erythropoietin receptor expression is concordant with erythropoietin but not with common beta chain expression in the rat brain throughout the life span.

J Comp Neurol 2009 Jun;514(4):403-14

Université de Lyon, Lyon, France.

Brain effects of erythropoietin (Epo) are proposed to involve a heteromeric receptor comprising the classical Epo receptor (Epo-R) and the common beta chain (betac). However, data documenting the pattern of betac gene expression in the healthy brain, in comparison with that of the Epo-R gene, are still lacking. The present study is the first to investigate at the same time betac, Epo-R, and Epo gene expression within different rat brain areas throughout the life span, from neonatal to elderly stages, using quantitative RT-PCR for transcripts. Corresponding proteins were localized by using immunohistochemistry. We demonstrate that the betac transcript level does not correlate with that of Epo-R or Epo, whereas the Epo-R transcript level strongly correlates with that of Epo throughout the life span in all brain structures analyzed. Both Epo and Epo-R were detected primarily in neurons. In the hippocampus, the greatest Epo-R mRNA levels were measured during the early postnatal period and in middle-aged rats, associated with an intense neuronal immunolabeling. Conversely, betac protein was barely detectable in the brain at all ages, even in neurons expressing high levels of Epo-R. Finally, betac transcript could not be detected in PC12 cells, even after nerve growth factor-induced neuritogenesis, which is a condition that dramatically enhances Epo-R transcript level. Altogether, our data suggest that most neurons are likely to express high levels of Epo-R but low, if not null, levels of betac. Given that Epo protects extended populations of neurons after injury, a yet-to-be-identified receptor heterocomplex including Epo-R may exist in the large population of brain neurons that does not express betac.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cne.22020DOI Listing
June 2009

ISG20L2, a novel vertebrate nucleolar exoribonuclease involved in ribosome biogenesis.

Mol Cell Proteomics 2008 Mar 6;7(3):546-59. Epub 2007 Dec 6.

Biomedical Proteomics Research Group, Département de Biologie Structurale et Bioinformatique, Centre Médical Universitaire, 1 Rue Michel Servet, 1211 Geneva 4, Switzerland.

Proteomics analyses of human nucleoli provided molecular bases for an understanding of the multiple functions fulfilled by these nuclear domains. However, the biological roles of about 100 of the identified proteins are unpredictable. The present study describes the functional characterization of one of these proteins, ISG20L2. We demonstrate that ISG20L2 is a 3' to 5' exoribonuclease involved in ribosome biogenesis at the level of 5.8 S rRNA maturation, more specifically in the processing of the 12 S precursor rRNA. The use of truncated forms of ISG20L2 demonstrated that its N-terminal half promotes the nucleolar localization and suggested that its C-terminal half bears the exoribonuclease activity. Identification of the binding partners of ISG20L2 confirmed its involvement in the biogenesis of the large ribosomal subunit. These results strongly support the notion that, in human, as it was demonstrated in yeast, 5.8 S rRNA maturation requires several proteins in addition to the exosome complex. Furthermore this observation greatly sustains the idea that the extremely conserved need for correctly processed rRNAs in vertebrates and yeast is achieved by close but different mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/mcp.M700510-MCP200DOI Listing
March 2008

Brain heparanase expression is up-regulated during postnatal development and hypoxia-induced neovascularization in adult rats.

J Neurochem 2008 Apr 6;105(1):34-45. Epub 2007 Nov 6.

Université de Lyon, Lyon, France.

Heparanase is an endo-beta-d-glucuronidase which specifically cleaves extracellular and cell surface heparan sulphates at intra-chain sites. Its enzymatic activity is strongly implicated in cell dissemination associated with tumor metastasis and inflammation. Indeed, heparanase gene is expressed in various tumors and its over-expression is correlated with increased tumor vascularity and metastatic potential of tumor cells. However, heparanase expression in non-invasive and non-immune tissue, including brain, has received less attention. Using RT-qPCR, western blot and histological analysis, we demonstrate in the adult rat that heparanase transcript is differentially expressed according to brain area, and that heparanase protein is mainly detected in neurons. Furthermore, we provide evidence that heparanase transcript and protein reach their greatest levels at early postnatal stages, in particular within the neocortex characterized by intensive structural plasticity. Using the in vitro model of PC12-induced neuronal differentiation, we suggest that developmental regulation of heparanase may coincide with axonal and dendritic pathfinding. At adulthood, we demonstrate that the increased heparanase transcript level correlates in the hippocampus with enhanced angiogenesis following repeated hypoxia exposures. Taken together, our results emphasize the potential importance of heparanase in brain homeostasis, both during development and adaptative responses to severe environmental challenges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2007.05116.xDOI Listing
April 2008

Regional age-related changes in neuronal nitric oxide synthase (nNOS), messenger RNA levels and activity in SAMP8 brain.

BMC Neurosci 2006 Dec 21;7:81. Epub 2006 Dec 21.

EA 3734, Faculty of Medecine, Claude Bernard University, 69373 Lyon, France.

Background: Nitric oxide (NO) is a multifunctional molecule synthesized by three isozymes of the NO synthase (NOSs) acting as a messenger/modulator and/or a potential neurotoxin. In rodents, the role of NOSs in sleep processes and throughout aging is now well established. For example, sleep parameters are highly deteriorated in senescence accelerated-prone 8 (SAMP8) mice, a useful animal model to study aging or age-associated disorders, while the inducible form of NOS (iNOS) is down-regulated within the cortex and the sleep-structures of the brainstem. Evidence is now increasing for a role of iNOS and resulting oxidative stress but not for the constitutive expressed isozyme (nNOS). To better understand the role of nNOS in the behavioural impairments observed in SAMP8 versus SAMR1 (control) animals, we evaluated age-related variations occurring in the nNOS expression and activity and nitrites/nitrates (NOx-) levels, in three brain areas (n = 7 animals in each group). Calibrated reverse transcriptase (RT) and real-time polymerase chain reaction (PCR) and biochemical procedures were used.

Results: We found that the levels of nNOS mRNA decreased in the cortex and the hippocampus of 8- vs 2-month-old animals followed by an increase in 12-vs 8-month-old animals in both strains. In the brainstem, levels of nNOS mRNA decreased in an age-dependent manner in SAMP8, but not in SAMR1. Regional age-related changes were also observed in nNOS activity. Moreover, nNOS activity in hippocampus was found lower in 8-month-old SAMP8 than in SAMR1, while in the cortex and the brainstem, nNOS activities increased at 8 months and afterward decreased with age in SAMP8 and SAMR1. NOx- levels showed profiles similar to nNOS activities in the cortex and the brainstem but were undetectable in the hippocampus of SAMP8 and SAMR1. Finally, NOx- levels were higher in the cortex of 8 month-old SAMP8 than in age-matched SAMR1.

Conclusion: Concomitant variations occurring in NO levels derived from nNOS and iNOS at an early age constitute a major factor of risk for sleep and/or memory impairments in SAMP8.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2202-7-81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1766358PMC
December 2006

Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus.

Neurobiol Dis 2007 Feb 12;25(2):412-26. Epub 2006 Dec 12.

Laboratory of Integrative Cellular and Molecular Physiology, Centre National de la Recherche Scientifique and Université Claude Bernard Lyon 1 UMR5123, Villeurbanne, France.

Neuroprotective functions of erythropoietin (Epo) are thought to involve a heteroreceptor composed of both Epo receptor (Epo-R) and common beta chain (betac). Here, we measured the response of hippocampal Epo system components (Epo, Epo-R and betac) during neurodegenerative processes following pilocarpine-induced status epilepticus (SE), and examined whether recombinant human Epo (rHuEpo) could support neuronal survival. We evidence that Epo is induced in astroglia following SE, in particular within areas displaying delayed neuronal death. In addition, we demonstrate for the first time that rHuEpo reduces considerably hippocampal neurodegeneration following SE. rHuEpo may thus supplement astroglial induction of Epo to promote enhanced hippocampal neuronal survival following SE. We also show that Epo-R is expressed by neurons and astrocytes mainly, while betac is barely detectable in basal conditions and induced in reactive microglia exclusively following SE. Altogether, our results suggest that Epo/rHuEpo exerts neuroprotection, through Epo-R signaling and independently of betac, and, therefore, may be anti-epileptogenic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2006.10.009DOI Listing
February 2007

Unexpected expression of orexin-B in basal conditions and increased levels in the adult rat hippocampus during pilocarpine-induced epileptogenesis.

Brain Res 2006 Sep 10;1109(1):164-75. Epub 2006 Aug 10.

Laboratoire de Physiologie Intégrative Cellulaire et Moléculaire, UMR 5123 CNRS and Université Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France.

Orexin-A (OX-A) and -B (OX-B) peptides present in the hippocampus are considered to be exclusively contained in fibers arising from hypothalamus neurons, which were established as the only source of orexins (OXs). Because OX-A is known to exert excitatory actions in the hippocampus, we hypothesized that the level of OXs targeted toward the hippocampus may be increased following status-epilepticus (SE)-induced epileptogenesis in the rat pilocarpine model of temporal lobe epilepsy. We found that tissue concentration of prepro-OX mRNA, which encodes for both peptides, rapidly decreased in the hypothalamus of rats having experienced pilocarpine-induced SE (Pilo-SE) followed by a reduced density of OX-A and OX-B immunopositive fibers arising from these neurons. By contrast, it was unexpected to detect within the hippocampus the presence of prepro-OX mRNA in basal conditions and to evidence its up-regulation during the 1- to 3-day period following Pilo-SE. The number of prepro-OX mRNA copies determined by real-time RT-PCR was approximately 50-fold lower in the hippocampus than that in the hypothalamus, precluding the use of in situ hybridization to localize the cells which synthesize the transcript within the hippocampus. The increase in prepro-OX mRNA level within the hippocampus was accompanied by the detection of OX-B-like immunoreactivity 2-3 days post-SE, not only in pyramidal neurons, granule cells and cell bodies resembling interneurons, but also in some astrocytes scattered throughout the hippocampus. The present data suggest that the gene encoding OXs can be activated in the hippocampus, which may play a role in the pathogenesis of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2006.06.075DOI Listing
September 2006

Effects of progressive and maximal exercise on plasma levels of adhesion molecules in athletes with sickle cell trait with or without alpha-thalassemia.

J Appl Physiol (1985) 2007 Jan 10;102(1):169-73. Epub 2006 Aug 10.

Equipe d'Accueil 647 Center of Research and Innovation on Sports, University of Lyon 1, Lyon, France.

The aim of the study was to examine the effects of exercise on soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Six athletes with SCT, seven athletes with both SCT and alpha-thalassemia (SCTAT), and seven control athletes (Cont) performed an incremental and maximal test on cycloergometer. Levels of sICAM-1 and sVCAM-1 were assessed at rest, immediately after the end of exercise, and 1, 2, and 24 h after exercise. Although Cont and SCTAT groups exhibited similar basal plasma levels of inflammatory and adhesion molecules, the SCT group had higher sVCAM-1 basal concentrations. Incremental exercise resulted in a significant increase of sVCAM-1 in all subjects, which remained elevated only in the SCT group during the recovery period. In conclusion, as sVCAM-1 increased with exercise and during the recovery period, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances and adhesive phenomena developing at rest and several hours after exercise. alpha-Thalassemia might be considered protective among exercising SCT subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00272.2006DOI Listing
January 2007

Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules.

Am J Physiol Renal Physiol 2006 Oct 4;291(4):F750-60. Epub 2006 Apr 4.

Centre de Génétique Moléculaire et Cellulaire, UMR 5534 du CNRS et de l'Université Claude Bernard 43, Bd du 11 novembre 1918, 69622 Villeurbanne Cédex, France.

Hypoxia has been suspected to trigger transdifferentiation of renal tubular cells into myofibroblasts in an epithelial-to-mesenchymal transition (EMT) process. To determine the functional networks potentially altered by hypoxia, rat renal tubule suspensions were incubated under three conditions of oxygenation ranging from normoxia (lactate uptake) to severe hypoxia (lactate production). Transcriptome changes after 4 h were analyzed on a high scale by restriction fragment differential display. Among 1,533 transcripts found, 42% were maximally expressed under severe hypoxia and 8% under mild hypoxia (Po(2) = 48 mmHg), suggesting two different levels of oxygen sensing. Normoxia was required for full expression of the proximal tubule-specific transcripts 25-hydroxyvitamin D 1-hydroxylase (Cyp27b1) and l-pyruvate kinase (Pklr), transcripts involved in tissue cohesion such as fibronectin (Fn1) and N-cadherin (Cdh2), and non-muscle-type myosin transcripts. Mild hypoxia increased myogenin transcript level. Conversely, severe hypoxia increased transcripts involved in extracellular matrix remodeling, those of muscle-type myosins, and others involved in creatine phosphate synthesis and lactate transport (Slc16a7). Accordingly, microscopy showed loss of tubule aggregation under hypoxia, without tubular disruption. Hypoxia also increased the levels of kidney-specific transcripts normally restricted to the less oxygenated medullary zone and others specific for the distal part of the nephron. We conclude that extensive oxygen supply to the kidney tubule favors expression of its differentiated functions specifically in the proximal tubule, whose embryonic origin is mesenchymal. The phenotype changes could potentially permit transient adaptation to hypoxia but also favor pathological processes such as tissue invasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00022.2006DOI Listing
October 2006

REM sleep control during aging in SAM mice: a role for inducible nitric oxide synthase.

Neurobiol Aging 2005 Nov-Dec;26(10):1375-84. Epub 2004 Dec 22.

Institut National de la Santé et de la Recherche Médicale EA3734, Department of Experimental Medicine, Faculty of Medecine, Claude Bernard University, Lyon Cedex 08 69373, France.

Evidence that nitric oxide (NO) is involved in the regulation of rapid-eye-movement sleep (REMS) is supported by recent studies. During aging, NO generation encounters marked changes mainly related to the activation of the inducible NO-synthase (iNOS). To investigate links existing between iNOS and REMS impairments related to aging, we examine the age-related variations occurring in: mRNA and activity of iNOS in brainstem and frontal cortex; sleep parameters under baseline and after treatment by a selective iNOS inhibitor (AMT) in Senescence Accelerated Mice (SAM). SAMR1 (control) mice are a model of aging while SAMP8 are adequate to study neurodegenerative processes. RT-PCR analysis does not reveal significant variation in iNOS mRNA expression in both strains. However, significant age-related increases in iNOS activity occur in SAMR1 but such variation is not observed in SAMP8. In baseline conditions, aging induces a slight increase in slow-wave sleep (SWS) amounts in both groups and deteriorates greatly REMS architecture in SAMP8 compared to SAMR1. AMT reduces REMS amounts for 4-6h after treatment in a dose and age-dependent manner in SAMR1. Almost no changes occur in SAMP8. Data reported suggest that NO derived from iNOS contributes to trigger and maintain REMS during aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2004.11.002DOI Listing
January 2006