Interventions to preserve functional capacities at advanced age are becoming increasingly importa... more Interventions to preserve functional capacities at advanced age are becoming increasingly important. So far, exercise provides the only means to counteract age‐related decrements in physical performance and muscle function. Unfortunately, the effectiveness of exercise interventions in elderly populations is hampered by reduced acceptance and compliance as well as disuse complications. We therefore studied whether application of interleukin‐6 (IL‐6), a pleiotropic myokine that is induced by skeletal muscle activity and exerts broad systemic effects in response to exercise, affects physical performance and muscle function alone or in combination with training in aged mice.
Oligodendrocytes generate and maintain myelin, which is essential for axonal function and protect... more Oligodendrocytes generate and maintain myelin, which is essential for axonal function and protection of the mammalian central nervous system. To advance our molecular understanding of differentiation by these cells, we screened libraries of pharmacologically active compounds and identified inducers of differentiation of Oli-neu, a stable cell line of mouse oligodendrocyte precursors (OPCs). We identified four broad classes of inducers, namely, forskolin/cAMP (protein kinase A activators), steroids (glucocorticoids and retinoic acid), ErbB2 inhibitors, and nucleoside analogs, and confirmed the activity of these compounds on rat primary oligodendrocyte precursors and mixed cortical cultures. We also analyzed transcriptional responses in the chemically induced mouse and rat OPC differentiation processes and compared these with earlier studies. We confirm the view that ErbB2 is a natural signaling component that is required for OPC proliferation, whereas ErbB2 inhibition or genetic knockdown results in OPC differentiation.
Direct application of brain-derived neurotrophic factor (BDNF) to the cut end of axotomized immat... more Direct application of brain-derived neurotrophic factor (BDNF) to the cut end of axotomized immature motor neurones had only transient survival-promoting effects. Therefore, we have examined whether additional delivery of BDNF with repeated subcutaneous injections (1 mg/ml) could potentiate this short-term rescue of the lesioned sciatic and facial motor neurones in neonatal rats. Direct application of BDNF combined with intermittent (3-day intervals) injections slightly improved motor neurone survival. However, when BDNF was injected daily in addition to the direct application, the number of surviving lesioned motor neurones was markedly reduced. These findings, corroborated by results in embryonic spinal cord cultures, show that a dose-dependent reversal of BDNF-mediated positive effects on motor neurones occurs in vivo.
Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of ... more Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of diabetes. Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need. Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration. IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multifunctional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion. IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to...
It has been shown that abnormalities in axonal transport occur in several mouse models with moton... more It has been shown that abnormalities in axonal transport occur in several mouse models with motoneuron degeneration and also in the human disease amyotrophic lateral sclerosis. In this report, we have examined the potential of neurotrophic factors to act on axonal transport properties in a mouse mutant, progressive motor neuronopathy (pmn). This mouse mutant has been characterized as a “dying-back ” motoneuronopathy, with a loss of motoneuron cell bodies and motor fibers. Retrograde transport to the spinal cord motoneurons was determined using fluorescent tracers either injected into the gastrocnemius muscle or applied directly onto the cut sciatic nerve. Because the rate of retrograde labeling was significantly reduced in the pmn, we examined the potential of neurotrophic factors to compensate for the impairment. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) but not glial-derived neurotrophic factor (GDNF) or nerve growth fa...
Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enha... more Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19 + B cells and in CD14 + monocytes, whereas CD4 + and CD8 + T cells were devoid of LRRK2 mRNA. Within CD14 + cells the CD14 + CD16 + sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14 + CD16- cells. However both populations expressed LRRK2 mRNA. As CD14 + CD16 + cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-c in particular robustly ...
La presente invention concerne l’utilisation du IL-17F, ou d’un agoniste de l'activite du IL-... more La presente invention concerne l’utilisation du IL-17F, ou d’un agoniste de l'activite du IL-17F, dans le traitement ou la prevention de maladies neurologiques.
L'invention concerne l'utilisation d'un isoforme d'IL18-BP qui ne se lie pas a IL... more L'invention concerne l'utilisation d'un isoforme d'IL18-BP qui ne se lie pas a IL18, ou d'un agoniste de celui-ci, dans le traitement ou la prevention d'une maladie neurologique et/ou inflammatoire. Les isoformes preferes selon l'invention comprennent IL-18BPb et IL-18BPd.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1998
It has been shown that abnormalities in axonal transport occur in several mouse models with moton... more It has been shown that abnormalities in axonal transport occur in several mouse models with motoneuron degeneration and also in the human disease amyotrophic lateral sclerosis. In this report, we have examined the potential of neurotrophic factors to act on axonal transport properties in a mouse mutant, progressive motor neuronopathy (pmn). This mouse mutant has been characterized as a "dying-back" motoneuronopathy, with a loss of motoneuron cell bodies and motor fibers. Retrograde transport to the spinal cord motoneurons was determined using fluorescent tracers either injected into the gastrocnemius muscle or applied directly onto the cut sciatic nerve. Because the rate of retrograde labeling was significantly reduced in the pmn, we examined the potential of neurotrophic factors to compensate for the impairment. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) but not glial-derived neurotrophic factor (GDNF) or nerve ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1996
Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has be... more Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has been shown to be a highly potent neurotrophic factor that enhances survival of various neuronal cell types including motoneurons. To assess its therapeutic potential in treating neurodegenerative diseases such as amyotrophic lateral sclerosis, we treated mutant mice displaying motoneuron degeneration (progressive motor neuropathy; pmn) with encapsulated GDNF-secreting cells. Effects of GDNF treatment on pmn/pmn mice were compared with previous results obtained with ciliary neurotrophic factor (CNTF) [Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Eur J Neurosci 7:1313-1322]. In contrast to CNTF, GDNF did not increase the lifespan of pmn/pmn mice. However, GDNF significantly reduced the loss of facial motoneurons by 50%, a value similar to what was observed when CNTF was administered to the pmn/pmn mice. Surprisingly, myelinated axon counts revealed that GDNF had no e...
Interventions to preserve functional capacities at advanced age are becoming increasingly importa... more Interventions to preserve functional capacities at advanced age are becoming increasingly important. So far, exercise provides the only means to counteract age‐related decrements in physical performance and muscle function. Unfortunately, the effectiveness of exercise interventions in elderly populations is hampered by reduced acceptance and compliance as well as disuse complications. We therefore studied whether application of interleukin‐6 (IL‐6), a pleiotropic myokine that is induced by skeletal muscle activity and exerts broad systemic effects in response to exercise, affects physical performance and muscle function alone or in combination with training in aged mice.
Oligodendrocytes generate and maintain myelin, which is essential for axonal function and protect... more Oligodendrocytes generate and maintain myelin, which is essential for axonal function and protection of the mammalian central nervous system. To advance our molecular understanding of differentiation by these cells, we screened libraries of pharmacologically active compounds and identified inducers of differentiation of Oli-neu, a stable cell line of mouse oligodendrocyte precursors (OPCs). We identified four broad classes of inducers, namely, forskolin/cAMP (protein kinase A activators), steroids (glucocorticoids and retinoic acid), ErbB2 inhibitors, and nucleoside analogs, and confirmed the activity of these compounds on rat primary oligodendrocyte precursors and mixed cortical cultures. We also analyzed transcriptional responses in the chemically induced mouse and rat OPC differentiation processes and compared these with earlier studies. We confirm the view that ErbB2 is a natural signaling component that is required for OPC proliferation, whereas ErbB2 inhibition or genetic knockdown results in OPC differentiation.
Direct application of brain-derived neurotrophic factor (BDNF) to the cut end of axotomized immat... more Direct application of brain-derived neurotrophic factor (BDNF) to the cut end of axotomized immature motor neurones had only transient survival-promoting effects. Therefore, we have examined whether additional delivery of BDNF with repeated subcutaneous injections (1 mg/ml) could potentiate this short-term rescue of the lesioned sciatic and facial motor neurones in neonatal rats. Direct application of BDNF combined with intermittent (3-day intervals) injections slightly improved motor neurone survival. However, when BDNF was injected daily in addition to the direct application, the number of surviving lesioned motor neurones was markedly reduced. These findings, corroborated by results in embryonic spinal cord cultures, show that a dose-dependent reversal of BDNF-mediated positive effects on motor neurones occurs in vivo.
Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of ... more Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of diabetes. Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need. Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration. IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multifunctional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion. IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to...
It has been shown that abnormalities in axonal transport occur in several mouse models with moton... more It has been shown that abnormalities in axonal transport occur in several mouse models with motoneuron degeneration and also in the human disease amyotrophic lateral sclerosis. In this report, we have examined the potential of neurotrophic factors to act on axonal transport properties in a mouse mutant, progressive motor neuronopathy (pmn). This mouse mutant has been characterized as a “dying-back ” motoneuronopathy, with a loss of motoneuron cell bodies and motor fibers. Retrograde transport to the spinal cord motoneurons was determined using fluorescent tracers either injected into the gastrocnemius muscle or applied directly onto the cut sciatic nerve. Because the rate of retrograde labeling was significantly reduced in the pmn, we examined the potential of neurotrophic factors to compensate for the impairment. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) but not glial-derived neurotrophic factor (GDNF) or nerve growth fa...
Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enha... more Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19 + B cells and in CD14 + monocytes, whereas CD4 + and CD8 + T cells were devoid of LRRK2 mRNA. Within CD14 + cells the CD14 + CD16 + sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14 + CD16- cells. However both populations expressed LRRK2 mRNA. As CD14 + CD16 + cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-c in particular robustly ...
La presente invention concerne l’utilisation du IL-17F, ou d’un agoniste de l'activite du IL-... more La presente invention concerne l’utilisation du IL-17F, ou d’un agoniste de l'activite du IL-17F, dans le traitement ou la prevention de maladies neurologiques.
L'invention concerne l'utilisation d'un isoforme d'IL18-BP qui ne se lie pas a IL... more L'invention concerne l'utilisation d'un isoforme d'IL18-BP qui ne se lie pas a IL18, ou d'un agoniste de celui-ci, dans le traitement ou la prevention d'une maladie neurologique et/ou inflammatoire. Les isoformes preferes selon l'invention comprennent IL-18BPb et IL-18BPd.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1998
It has been shown that abnormalities in axonal transport occur in several mouse models with moton... more It has been shown that abnormalities in axonal transport occur in several mouse models with motoneuron degeneration and also in the human disease amyotrophic lateral sclerosis. In this report, we have examined the potential of neurotrophic factors to act on axonal transport properties in a mouse mutant, progressive motor neuronopathy (pmn). This mouse mutant has been characterized as a "dying-back" motoneuronopathy, with a loss of motoneuron cell bodies and motor fibers. Retrograde transport to the spinal cord motoneurons was determined using fluorescent tracers either injected into the gastrocnemius muscle or applied directly onto the cut sciatic nerve. Because the rate of retrograde labeling was significantly reduced in the pmn, we examined the potential of neurotrophic factors to compensate for the impairment. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) but not glial-derived neurotrophic factor (GDNF) or nerve ...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1996
Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has be... more Glial cell line-derived neurotrophic factor (GDNF), a member of the TG F-beta superfamily, has been shown to be a highly potent neurotrophic factor that enhances survival of various neuronal cell types including motoneurons. To assess its therapeutic potential in treating neurodegenerative diseases such as amyotrophic lateral sclerosis, we treated mutant mice displaying motoneuron degeneration (progressive motor neuropathy; pmn) with encapsulated GDNF-secreting cells. Effects of GDNF treatment on pmn/pmn mice were compared with previous results obtained with ciliary neurotrophic factor (CNTF) [Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Eur J Neurosci 7:1313-1322]. In contrast to CNTF, GDNF did not increase the lifespan of pmn/pmn mice. However, GDNF significantly reduced the loss of facial motoneurons by 50%, a value similar to what was observed when CNTF was administered to the pmn/pmn mice. Surprisingly, myelinated axon counts revealed that GDNF had no e...
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Papers by Yves Sagot