References of "Malgrange, Brigitte"
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See detailAdult neurogenesis and the diseased brain.
Vandenbosch, Renaud ULg; Borgs, Laurence ULg; Beukelaers, Pierre ULg et al

in Current Medicinal Chemistry (2009), 16(6), 652-66

For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification ... [more ▼]

For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification of adult neural stem cells (NSCs) and evidence regarding a continuous production of neurons throughout life in the dentate gyrus (DG) and the subventricular zone of the lateral ventricles (SVZ), have provided new hopes for the development of novel therapeutic strategies to induce regeneration in the damaged brain. Moreover, proofs have accumulated this last decade that endogenous stem/progenitor cells of the adult brain have an intrinsic capacity to respond to brain disorders. Here, we first briefly summarize our current knowledge related to adult neurogenesis before focusing on the behaviour of adult neural stem/progenitors cells following stroke and seizure, and describe some of the molecular cues involved in the response of these cells to injury. In the second part, we outline the consequences of three main neurodegenerative disorders on adult neurogenesis and we discuss the potential therapeutic implication of adult neural stem/progenitors cells during the course of these diseases. [less ▲]

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See detailCell "circadian" cycle: new role for mammalian core clock genes.
Borgs, Laurence ULg; Beukelaers, Pierre ULg; Vandenbosch, Renaud ULg et al

in Cell Cycle (Georgetown, Tex.) (2009), 8(6), 832-7

In mammals, 24 hours rhythms are organized as a biochemical network of molecular clocks that are operative in all tissues, with the master clock residing in the hypothalamic suprachiasmatic nucleus (SCN ... [more ▼]

In mammals, 24 hours rhythms are organized as a biochemical network of molecular clocks that are operative in all tissues, with the master clock residing in the hypothalamic suprachiasmatic nucleus (SCN). The core pacemakers of these clocks consist of auto-regulatory transcriptional/post-transcriptional feedback loops. Several lines of evidence suggest the existence of a crosstalk between molecules that are responsible for the generation of circadian rhythms and molecules that control the cell cycle progression. In addition, highly specialized cell cycle checkpoints involved in DNA repair after damage seem also, at least in part, mediated by clock proteins. Recent studies have also highlighted a putative connection between clock protein dysfunction and cancer progression. This review discusses the intimate relation that exists between cell cycle progression and components of the circadian machinery. [less ▲]

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See detailPeriod 2 regulates neural stem/progenitor cell proliferation in the adult hippocampus.
Borgs, Laurence ULg; Beukelaers, Pierre ULg; Vandenbosch, Renaud ULg et al

in BMC Neuroscience (2009), 10

BACKGROUND: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light ... [more ▼]

BACKGROUND: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG. RESULTS: In contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene (Per2Brdm1), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death. CONCLUSION: Taken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice. [less ▲]

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See detailSox10 promotes the survival of cochlear progenitors during the establishment of the organ of Corti
Breuskin, Ingrid ULg; Bodson, Morgan ULg; Thelen, Nicolas ULg et al

in Developmental Biology (2009), 15(335), 327-339

Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show that ... [more ▼]

Transcription factors of the SoxE family are critical players that underlie various embryological processes. However, little is known about their function during inner ear development. Here, we show that Sox10 is initially expressed throughout the otic vesicle epithelium and becomes later restricted to supporting cells as cell differentiation proceeds in the organ of Corti. Morphological analyses of Sox10 mutant mice reveal a significant shortening of the cochlear duct likely resulting from the progressive depletion of cochlear progenitors. While Sox10 appears dispensable for the differentiation and patterning of the inner ear prosensory progenitors, our data support a critical role for this transcription factor in the promotion of their survival. We provide genetic evidences that Sox10, in a concentration-dependant manner, could play a role in the regulation of Jagged1, a gene known to be important for inner ear prosensory development. Together, our results demonstrate that Sox10 regulates the biology of early cochlear progenitors during inner ear development, but, in contrast to neural crest-derived cells, this transcription factor is dispensable for their differentiation. Evidence also suggests that this effect occurs via the activation of the Jagged1 gene. [less ▲]

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See detailEarly identification of inner pillar cells during rat cochlear development.
Thelen, Nicolas ULg; Breuskin, Ingrid ULg; Malgrange, Brigitte ULg et al

in Cell & Tissue Research (2009), 337(1), 1-14

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Here, we examine its spatio-temporal development ... [more ▼]

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Here, we examine its spatio-temporal development in rats from embryonic day 16 (E16) to E19 by using cytochemical and immunocytochemical methods at the light- and electron-microscope levels. We demonstrate that the organ of Corti develops from a non-proliferating cell zone that is located in the junctional region between two edges of the dorsal epithelium of the cochlear duct. We also reveal that the first cells to develop in this zone are the inner pillar cells, a particular type of non-sensory supporting cell, which arise in the base of the cochlear duct at the boundary between the two ridges at E16. Cell differentiation in this prosensory region continues according to a base-to-apex gradient; the inner hair cells appear in the greater epithelial ridge at E17 and the outer hair cells in the lesser epithelial ridge at E18. At E19, the various cell types of the organ of Corti are in place. Finally, we show that unlike the development of all the supporting cell types of the organ of Corti, the development of inner pillar cells within the prosensory domain seems not to involve Notch1 activation. These results highlight the central role that the inner pillar cells probably play in the development of the organ of Corti. [less ▲]

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See detailNew insights in mammalian auditory organ development
Thelen, Nicolas ULg; Malgrange, Brigitte ULg; Thiry, Marc

Conference (2008, October 30)

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Using cytochemical and immunohistochemical methods ... [more ▼]

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far from being elucidated. Using cytochemical and immunohistochemical methods at the light and electron microscope levels, we examined its spatiotemporal development in rats from embryonic day 16 (E16) to E19. At E16, whatever the region of the cochlear studied (base, middle, apex), the organ of Corti was not present. We demonstrate that the organ of Corti develops from a non-proliferative cell zone that is located in the junctional region between the greater epithelial ridge and the lesser epithelial ridge of the cochlear duct and that is characterized by the presence of numerous microvilli. Using the periodic acid-thiocarbohydrazide-silver proteinate method, we revealed that the first cells to develop in this zone are the inner pillar cells, a particular type of nonsensory supporting cells. They arise in the base of the cochlear duct at the boundary between the two ridges at E16. The cell differentiation in this prosensory region continues according to a base-to-apex gradient, the inner hair cells appearing in the greater epithelial ridge at E17 and the outer hair cells in the lesser epithelial ridge at E18. At E19, all the different cell types of the organ of Corti are well in place. We also showed that the development of the inner pillar cells within the prosensory region does not involve Notch1 signaling. These results highlight the central role that the inner pillar cells could play in the development of the organ of Corti. [less ▲]

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See detailStrategies to Regenerate Hair Cells: Identification of Progenitors and Critical Genes
Breuskin, Ingrid ULg; Bodson, Morgan ULg; Thelen, Nicolas ULg et al

in Hearing Research (2008), 236(1-2), 1-10

Deafness commonly results from a lesion of the sensory cells and/or of the neurons of the auditory part of the inner ear. There are currently no treatments designed to halt or reverse the progression of ... [more ▼]

Deafness commonly results from a lesion of the sensory cells and/or of the neurons of the auditory part of the inner ear. There are currently no treatments designed to halt or reverse the progression of hearing loss. A key goal in developing therapy for sensorineural deafness is the identification of strategies to replace lost hair cells. In amphibians and birds, a spontaneous post-injury regeneration of all inner ear sensory hair cells occurs. In contrast, in the mammalian cochlea, hair cells are only produced during embryogenesis. Many studies have been carried out in order to demonstrate the persistence of endogenous progenitors. The present review is first focused on the occurrence of spontaneous supernumerary hair cells and on nestin positive precursors found in the organ of Corti. A second approach to regenerating hair cells would be to find genes essential for their differentiation. This review will also focus on critical genes for embryonic hair cell formation such as the cell cycle related proteins, the Atoh1 gene and the Notch signaling pathway. Understanding mechanisms that underlie hair cell production is an essential prerequisite to defining therapeutic strategies to regenerate hair cells in the mature inner ear. [less ▲]

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See detailCdk2 Is Dispensable for Adult Hippocampal Neurogenesis
Vandenbosch, Renaud ULg; Borgs, Laurence ULg; Beukelaers, Pierre ULg et al

in Cell Cycle (Georgetown, Tex.) (2007), 6(24), 3065-9

Granule neurons of the dentate gyrus (DG) of the hippocampus undergo continuous renewal throughout life. Among cell cycle regulators, cyclin-dependent kinase 2 (Cdk2) is considered as a major regulator of ... [more ▼]

Granule neurons of the dentate gyrus (DG) of the hippocampus undergo continuous renewal throughout life. Among cell cycle regulators, cyclin-dependent kinase 2 (Cdk2) is considered as a major regulator of S-phase entry. We used Cdk2-deficient mice to decipher the requirement of Cdk2 for the generation of new neurons in the adult hippocampus. The quantification of cell cycle markers first revealed that the lack of Cdk2 activity does not influence spontaneous or seizure-induced proliferation of neural progenitor cells (NPC) in the adult DG. Using bromodeoxyuridine incorporation assays, we showed that the number of mature newborn granule neurons generated de novo was similar in both wild-type (WT) and Cdk2-deficient adult mice. Moreover, the apparent lack of cell output reduction in Cdk2(-/-) mice DG did not result from a reduction in apoptosis of newborn granule cells as analyzed by TUNEL assays. Our results therefore suggest that Cdk2 is dispensable for NPC proliferation, differentiation and survival of adult-born DG granule neurons in vivo. These data emphasize that functional redundancies between Cdks also occur in the adult brain at the level of neural progenitor cell cycle regulation during hippocampal neurogenesis. [less ▲]

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See detailNew insights into peripherin expression in cochlear neurons
Lallemend, François; Vandenbosch, Renaud ULg; Hadjab, S. et al

in Neuroscience (2007), 150(1), 212-222

Peripherin is an intermediate filament protein that is expressed in peripheral and enteric neurons. In the cochlear nervous system, peripherin expression has been extensively used as a differentiation ... [more ▼]

Peripherin is an intermediate filament protein that is expressed in peripheral and enteric neurons. In the cochlear nervous system, peripherin expression has been extensively used as a differentiation marker by preferentially labeling the type II neuronal population at adulthood, but yet without knowing its function. Since the expression of peripherin has been associated in time with the process of axonal extension and during regeneration of nerve fibers in other systems, it was of interest to determine whether peripherin expression in cochlear neurons was a static phenotypic trait or rather prone to modifications following nerve injury. In the present study, we first compared the expression pattern of peripherin and beta III-tubulin from late embryonic stages to the adult in rat cochlea. The staining for both proteins was seen before birth within all cochlear neurons. By birth, and for 2 or 3 days, peripherin expression was gradually restricted to the type II neuronal population and their projections. In contrast, from postnatal day (P) 10 onwards, while the expression of beta III-tubulin was still found in projections of all cochlear neurons, only the type I population had beta III-tubulin immunoreactivity in their cell bodies. We next investigated the expression of peripherin in axotomized cochlear neurons using an organotypic explant model. Peripherin expression was surprisingly re-expressed in a vast majority of neurons after axotomy. In parallel, the expression and localization of beta III-tubulin and peripherin in dissociated cultures of cochlear neurons were studied. Both proteins were distributed along the entire neuronal length but exhibited complementary distribution, especially within the projections. Moreover, peripherin immunoreactivity was still abundant in the growth cone, whereas that of beta III-tubulin was decreasing at this compartment. Our findings are consistent with a model in which peripherin plays an important structural role in cochlear neurons and their projections during both development and regenerative processes and which is compatible with the assumption that frequently developmentally regulated factors are reactivated during neuronal regeneration. [less ▲]

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See detailAn atypical cell during development of the auditory organ : the inner pillar cell
Thelen, Nicolas ULg; Malgrange, Brigitte ULg; Thiry, Marc ULg

Poster (2007, September)

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far to be elucidated. Using cytochemical and immunohistochemical methods at ... [more ▼]

Although the structure of the auditory organ in mature mammals, the organ of Corti, is clearly established, its development is far to be elucidated. Using cytochemical and immunohistochemical methods at the light and electron microscope levels, we examined its spatiotemporal development in rats from embryonic day 16 (E16) to E19. <br />At E16, whatever the region of the cochlear studied (base, middle, apex), the organ of Corti is not present. We demonstrate that the organ of Corti develops from a non-proliferative cell zone that is located in the junctional region between the greater epithelial ridge and the lesser epithelial ridge of the cochlear duct and that is characterized by the presence of numerous microvilli. Using the periodic acid-thiocarbohydrazide-silver proteinate method, we reveal that the first cells to develop in this zone are the inner pillar cells, a particular type of nonsensory supporting cells; they arise in the base of the cochlear duct at the boundary between the two ridges at E16. The cell differentiation in this prosensory region continues according to a base-to-apex gradient, the inner hair cells appear in the greater epithelial ridge at E17 and the outer hair cells in the lesser epithelial ridge at E18. At E19, all the different cell types of the organ of Corti are well in place. We also show that the development of the inner pillar cells within the prosensory region does not involve Notch1 signaling. These results highlight the central role that cells could play the inner pillar in the organ of Corti development. [less ▲]

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See detailVector-mediated delivery of bcl-2 prevents degeneration of auditory hair cells and neurons after injury.
Staecker, Hinrich; Liu, Wei; Malgrange, Brigitte ULg et al

in ORL (2007), 69(1), 43-50

OBJECTIVE: To test the hypothesis that bcl-2 prevents oxidative stress-induced apoptosis of auditory sensory cells in explants of the organ of Corti and dissociated cell cultures of the spiral ganglion ... [more ▼]

OBJECTIVE: To test the hypothesis that bcl-2 prevents oxidative stress-induced apoptosis of auditory sensory cells in explants of the organ of Corti and dissociated cell cultures of the spiral ganglion. METHODS: Organ of Corti explants and dissociated spiral ganglion cell cultures obtained from 3-day-old (P3) rats or adult spiral ganglion cell cultures from 28-day-old (P28) rats were transduced with vectors containing a human bcl-2 gene. Cultures were then exposed to neomycin, cisplatin or subjected to withdrawal of neurotrophin supplementation. Outcome measures included hair cell and neuron counts, mitochondrial membrane potential and a histological measure of apoptosis. RESULTS: Expression of bcl-2 in the organ of Corti explants and neuronal cell cultures provided a significant level of protection against cell death. Bcl-2 expression in the organ of Corti explants also protected mitochondria from loss of membrane potential and blocked an early step in the commitment of hair cells to apoptosis. CONCLUSION: Expression of bcl-2 in cochlear tissues protects sensory cells from a variety of insults that have been demonstrated to damage the inner ear. [less ▲]

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See detailPrenatal development study of rat corti organ at the morphological level
Thelen, Nicolas ULg; Malgrange, Brigitte ULg; Thiry, Marc ULg

Poster (2006, September)

Although the structural organization of the mature Corti organ is generally well defined, little is known about its prenatal development. Here, we have examined by photonic and electron transmission ... [more ▼]

Although the structural organization of the mature Corti organ is generally well defined, little is known about its prenatal development. Here, we have examined by photonic and electron transmission microscopies the morphological changes occurring in the cochlear epithelium from the embryonic day 16 to 19 in rat. Moreover, we have used the periodic acid-thiocarbohydrazide-silver proteinate method to detect the glycogen particles on semithin and ultrathin sections of the cochlear duct. <br />At the embryonic day 16 (E16), whatever the region of the cochlear studied (base, medium, apex), the organ of Corti is not present. The cochlear epithelium appears as a pseudostratified epithelium formed formed by two distinct regions according to the presence or the absence of microvilli at the apical surface of cells. The region with the microvilli is on the modiolar side and the presence of microvilli is a characteristic of cells in the greater epithelial ridge (GER). In basal part of the cochlear duct, glycogen particles are visible on ultrathin sections in only one cell. On both sides of this cell, apical part of the epithelium shows microvilli. At E17, on semithin sections of basal and medium parts of cochlear duct, one cell visible on the whole height of the epithelium shows rich content in glycogen . At E18, in the majority of sections realized at the base and medium of the cochlear canal, the organ of Corti is relatively well recognizable. We distinguish principally the inner hair cells but also to a lesser extent the outer hair cells as well as the supporting cells (pillar, phalengeal and Deiters cells).We show that only the pillar cells have a rich content in glycogen. At E19, the organ of Corti is clearly recognizable in all the basal and medium parts of the cochlear duct. By contrast, it is yet differenciated in the apex. <br />These data seem to indicate that the Corti organ in rat develops from base to apex in the greater epithelial ridge starting by the pillar cells. [less ▲]

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See detailDelayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages
Bouhy, Delphine; Malgrange, Brigitte ULg; Multon, Sylvie ULg et al

in FASEB Journal (2006), 20(8), 12391241

Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the ... [more ▼]

Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 3-4 wk after a compression-injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in the same paraplegia model and in cell cultures. There was a significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2 mu g GM-CSF, which also increased significantly the expression of Cr3 and brain-derived neurotrophic factor ( BDNF) by macrophages at the lesion site. At longer survival delays, axonal regeneration was significantly enhanced in GMCSF-treated rats. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM-CSF and neurons cocultured with microglial cells activated by GM-CSF generated more neurites, an effect blocked by a BDNF antibody. These experiments suggest that GM-CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.-Bouhy, D., Malgrange, B., Multon, S., Poirrier, A. L., Scholtes, F., Schoenen, J., Franzen, R. Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages. [less ▲]

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See detailThe Yin and Yang of cell cycle progression and differentiation in the oligodendroglial lineage
Nguyen, Laurent ULg; Borgs, Laurence ULg; Vandenbosch, Renaud ULg et al

in Mental Retardation & Developmental Disabilities Research Reviews (2006), 12(2), 85-96

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor ... [more ▼]

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white matter, contact the axon, and differentiate into myelin-forming oligodendrocytes. Multiple mechanisms underlie the eventual progressive deterioration that typifies the natural history of developmental demyelination in LID and PVL and of adult-onset demyelination in MS. Over the past few years, pathophysiological studies have mostly focused on seeking abnormalities that impede oligodendroglial maturation at the level of migration, myelination, and survival. In contrast, there has been a strikingly lower interest for early proliferative and differentiation events that are likely to be equally critical for white matter development and myelin repair. This review highlights the Yin and Yang principles of interactions between intrinsic factors that coordinately regulate progenitor cell division and the onset of differentiation, i.e. the initial steps of oligodendrocyte lineage progression that are obviously crucial in health and diseases. (C) 2006 Wiley-Liss, Inc. [less ▲]

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See detailActivation of protein kinase CbetaI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons
Lallemend, François; Hadjab, Saida; Hans, Grégory ULg et al

in Journal of Cell Science (2005), 118(19), 4511-4525

In mammals, degeneration of peripheral auditory neurons constitutes one of the main causes of sensorineural hearing loss. Unfortunately, to date, pharmacological interventions aimed at counteracting this ... [more ▼]

In mammals, degeneration of peripheral auditory neurons constitutes one of the main causes of sensorineural hearing loss. Unfortunately, to date, pharmacological interventions aimed at counteracting this condition have not presented complete effectiveness in protecting the integrity of cochlear neural elements. In this context, the protein kinase C (PKC) family of enzymes are important signalling molecules that play a role in preventing neurodegeneration after nervous system injury. The present study demonstrates, for the first time, that the PKC signalling pathway is directly neurotrophic to axotomised spiral ganglion neurons (SGNs). We found that PKC beta I was strictly expressed by postnatal and adult SGNs both in situ and in vitro. In cultures of SGNs, we observed that activators of PKC, such as phorbol esters and bryostatin 1, induced neuronal survival and neurite regrowth in a manner dependent on the activation of PKC beta I. The neuroprotective effects of PKC activators were suppressed by pre-treatment with LY294002 (a PI3K inhibitor) and with U0126 (a MEK inhibitor), indicating that PKC activators promote the survival and neurite outgrowth of SGNs by both PI3K/Akt and MEK/ERK-dependent mechanisms. In addition, whereas combining the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) was shown to provide only an additive effect on SGN survival, the interaction between PKC and neurotrophin signalling gave rise to a synergistic increase in SGN survival. Taken together, the data indicate that PKC beta I activation represents a key factor for the protection of the integrity of neural elements in the cochlea. [less ▲]

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See detailPeripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression
Hans, Grégory ULg; Wislet, Sabine ULg; Lallemend, François et al

in Biochemical Pharmacology (2005), 69(5), 819-830

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising ... [more ▼]

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 And Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 54864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells. (C) 2004 Elsevier Inc. All rights reserved. [less ▲]

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See detailbeta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway
Hans, Grégory ULg; Malgrange, Brigitte ULg; Lallemend, François et al

in Neuropharmacology (2005), 48(1), 105-117

N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities ... [more ▼]

N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities with the synthetic neurotoxin 1-methy14-phenyl-1,2,3,6-tetrahydropyridine (MPTP), harman and norharman compounds have been proposed to be involved in the pathogenesis of Parkinson's disease. While also structurally related, betaCCB has received much less interest in that respect although we had previously demonstrated that it induces the apoptotic cell death of cultured cerebellar granule neurons (CGNs). Herein, we have investigated the molecular events leading to CGN apoptosis upon betaCCB treatment. We first demonstrated that betaCCB-induced apoptosis occurs in neurons only, most likely as a consequence of a specific neuronal uptake as shown using binding/uptake experiments. Then we observed that, in betaCCB-treated CGNs, caspases 9, 3 and 8 were successively activated, suegesing an activation of the mitochondrial pathway. Consistently, betaCCB also induced the release from the mitochondrial intermembrane space of two pro-apoptotic factors. i.e. cytochrome c and apotptosis inducing factor (AIF). Interestingly, no mitochondrial membrane depolarisation was associated with this release. suggesting a mitochondrial permeability transition pore-independent mechanism. The absence of any neuroprotective effect provided by two mPTP inhibitors. i.e. cyclosporine A and bongkrekic acid. further supported this hypothesis. Together. these results show that betaCCB is specifically taken up by neuronal cells where it triggers a specific permeabilization of the outer mitochondrial membrane and a subsequent apoptotic cell death. (C) 2004 Elsevier Ltd. All rights reserved. [less ▲]

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