The Experts below are selected from a list of 411 Experts worldwide ranked by ideXlab platform
Marie-christine Tonon - One of the best experts on this subject based on the ideXlab platform.
-
Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases.
Frontiers in endocrinology, 2020Co-Authors: Olfa Masmoudi-kouki, Jérôme Leprince, Benjamin Lefranc, Julien Chuquet, Yosra Hamdi, Ikram Ghouili, Seyma Bahdoudi, Amira Namsi, Taoufik Ghrairi, Marie-christine TononAbstract:Octadecaneuropeptide (ODN) and its precursor diazepam-binding inhibitor (DBI) are peptides belonging to the family of Endozepines. Endozepines are exclusively produced by astroglial cells in the central nervous system of mammals, and their release is regulated by stress signals and neuroactive compounds. There is now compelling evidence that the gliopeptide ODN protects cultured neurons and astrocytes from apoptotic cell death induced by various neurotoxic agents. In vivo, ODN causes a very strong neuroprotective action against neuronal degeneration in a mouse model of Parkinson's disease. The neuroprotective activity of ODN is based on its capacity to reduce inflammation, apoptosis, and oxidative stress. The protective effects of ODN are mediated through its metabotropic receptor. This receptor activates a transduction cascade of second messengers to stimulate protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathways, which in turn inhibits the expression of proapoptotic factor Bax and the mitochondrial apoptotic pathway. In N2a cells, ODN also promotes survival and stimulates neurite outgrowth. During the ODN-induced neuronal differentiation process, numerous mitochondria and peroxisomes are identified in the neurites and an increase in the amount of cholesterol and fatty acids is observed. The antiapoptotic and neurotrophic properties of ODN, including its antioxidant, antiapoptotic, and pro-differentiating effects, suggest that this gliopeptide and some of its selective and stable derivatives may have therapeutic value for the treatment of some neurodegenerative diseases.
-
Glial Endozepines and energy balance: Old peptides with new tricks.
Glia, 2020Co-Authors: Bruno Lebrun, Jérôme Leprince, Marie-christine Tonon, Vincent Prévot, Manon Barbot, Jean-denis TroadecAbstract:The contribution of neuroglial interactions to the regulation of energy balance has gained increasing acceptance in recent years. In this context, Endozepines, endogenous analogs of benzodiazepine derived from diazepam-binding inhibitor, are now emerging as major players. Produced by glial cells (astrocytes and tanycytes), Endozepines have been known for two decades to exert potent anorexigenic effects by acting at the hypothalamic level. However, it is only recently that their modes of action, including the mechanisms by which they modulate energy metabolism, have begun to be elucidated. The data available today are abundant, significant, and sometimes contradictory, revealing a much more complex regulation than initially expected. Several mechanisms of action of Endozepines seem to coexist at the central level, particularly in the hypothalamus. The brainstem has also recently emerged as a potential site of action for Endozepines. In addition to their central anorexigenic effects, Endozepines may also display peripheral effects promoting orexigenic actions, adding to their complexity and raising yet more questions. In this review, we attempt to provide an overview of our current knowledge in this rapidly evolving field and to pinpoint questions that remain unanswered.
-
Endozepines and their receptors: Structure, functions and pathophysiological significance
Pharmacology and Therapeutics, 2020Co-Authors: Marie-christine Tonon, Hubert Vaudry, Florent Guillebaud, Damien Lanfray, Fabrice Morin, Olfa Masmoudi-kouki, David Vaudry, Julien Chuquet, Jinjiang Fan, Vincent PrévotAbstract:The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « Endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that Endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein (PBR/TSPO), and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, Endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, Endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, Endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, Endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of Endozepines and discusses the physiopathological implications of these regulatory gliopeptides.
-
Endozepines and their receptors: Structure, functions and pathophysiological significance.
Pharmacology & therapeutics, 2019Co-Authors: Marie-christine Tonon, Hubert Vaudry, Florent Guillebaud, Damien Lanfray, Fabrice Morin, Olfa Masmoudi-kouki, David Vaudry, Julien Chuquet, Jinjiang Fan, Vincent PrévotAbstract:The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « Endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that Endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein, and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, Endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, Endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, Endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, Endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of Endozepines and discuss the physiopathological implications of these regulatory gliopeptides.
-
Glial Endozepines Inhibit Feeding-Related Autonomic Functions by Acting at the Brainstem Level
Frontiers in Neuroscience, 2017Co-Authors: Florent Guillebaud, Jérôme Leprince, Marie-christine Tonon, Clémence Girardet, Anne Abysique, Stéphanie Gaigé, Rym Barbouche, Jérémy Verneuil, Andre Jean, Michel DallaportaAbstract:Endozepines are endogenous ligands for the benzodiazepine receptors and also target a still unidentified GPCR. The Endozepine octadecaneuropeptide (ODN), an endoproteolytic processing product of the diazepam-binding inhibitor (DBI) was recently shown to be involved in food intake control as an anorexigenic factor through ODN-GPCR signaling and mobilization of the melanocortinergic signaling pathway. Within the hypothalamus, the DBI gene is mainly expressed by non-neuronal cells such as ependymocytes, tanycytes, and protoplasmic astrocytes, at levels depending on the nutritional status. Administration of ODN C-terminal octapeptide (OP) in the arcuate nucleus strongly reduces food intake. Up to now, the relevance of extrahypothalamic targets for Endozepine signaling-mediated anorexia has been largely ignored. We focused our study on the dorsal vagal complex located in the caudal brainstem. This structure is strongly involved in the homeostatic control of food intake and comprises structural similarities with the hypothalamus. In particular, a circumventricular organ, the area postrema (AP) and a tanycyte-like cells forming barrier between the AP and the adjacent nucleus tractus solitarius (NTS) are present. We show here that DBI is highly expressed by ependymocytes lining the fourth ventricle, tanycytes-like cells, as well as by proteoplasmic astrocytes located in the vicinity of AP/NTS interface. ODN staining observed at the electron microscopic level reveals that ODN-expressing tanycyte-like cells and protoplasmic astrocytes are sometimes found in close apposition to neuronal elements such as dendritic profiles or axon terminals. Intracerebroventricular injection of ODN or OP in the fourth ventricle triggers c-Fos activation in the dorsal vagal complex and strongly reduces food intake. We also show that, similarly to leptin, ODN inhibits the swallowing reflex when microinjected into the swallowing pattern generator located in the NTS. In conclusion, we hypothesized that ODN expressing cells located at the AP/NTS interface could release ODN and modify excitability of NTS neurocircuitries involved in food intake control.
Hubert Vaudry - One of the best experts on this subject based on the ideXlab platform.
-
Endozepines and their receptors: Structure, functions and pathophysiological significance
Pharmacology and Therapeutics, 2020Co-Authors: Marie-christine Tonon, Hubert Vaudry, Florent Guillebaud, Damien Lanfray, Fabrice Morin, Olfa Masmoudi-kouki, David Vaudry, Julien Chuquet, Jinjiang Fan, Vincent PrévotAbstract:The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « Endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that Endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein (PBR/TSPO), and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, Endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, Endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, Endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, Endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of Endozepines and discusses the physiopathological implications of these regulatory gliopeptides.
-
Endozepines and their receptors: Structure, functions and pathophysiological significance.
Pharmacology & therapeutics, 2019Co-Authors: Marie-christine Tonon, Hubert Vaudry, Florent Guillebaud, Damien Lanfray, Fabrice Morin, Olfa Masmoudi-kouki, David Vaudry, Julien Chuquet, Jinjiang Fan, Vincent PrévotAbstract:The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « Endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that Endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein, and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, Endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, Endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, Endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, Endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of Endozepines and discuss the physiopathological implications of these regulatory gliopeptides.
-
Neuroprotection with the Endozepine Octadecaneuropeptide, ODN.
Current pharmaceutical design, 2019Co-Authors: Olfa Masmoudi-kouki, Helene Castel, Mohamed Amri, Hubert Vaudry, Jérôme Leprince, Yosra Hamdi, Ikram Ghouili, Seyma Bahdoudi, Hadhemi Kaddour, David VaudryAbstract:The term Endozepines designates a family of astroglia-secreted proteins including the diazepambinding inhibitor (DBI) and its processing products, which have been originally isolated and characterized as endogenous ligands of benzodiazepine receptors. It is now clearly established that the octadecaneuropeptide ODN (DBI33-50), acting through the central-type benzodiazepine receptor or a metabotropic receptor, exerts important functions such as proconflict behavior, induction of anxiety, inhibition of pentobarbital-provoked sleep, decrease of water consumption and reduction of food intake. To mediate its effects, ODN regulates both glial cell and neuronal activities by acting on neurosteroid biosynthesis and/or neuropeptide expression. In addition, ODN stimulates astrocyte proliferation and protects both neurons and astrocytes from oxidative stress-induced cell death. The antiapoptotic effect of ODN on neural cells is mediated through activation of the ODN metabotropic receptor positively coupled to PKA, PKC and MAPK/ERK transduction pathways, which ultimately reduces the pro-apoptotic gene Bax and stimulates Bcl-2 expressions, and inhibits intracellular reactive oxygen species accumulation. The imbalance in favor of Bcl2 promotes mitochondria functions and blocks in turn caspases activation while at the same time, ODN also activates the endogenous antioxidant system i.e. glutathione biosynthesis, and expression and activities of antioxidant enzymes. In cultured astrocytes, DBI expression is up-regulated during moderate oxidative stress, and authentic ODN production is increased, suggesting that ODN may act as a paracrine factor protecting neighboring neurons. Taken together, the remarkable effect of ODN on the apoptotic cascade suggests that innovative ODN derivatives could potentially be useful for treatment of cerebral injuries involving oxidative stress and neurodegeneration.
-
Gliotransmission and Brain Glucose–Sensing Critical Role of Endozepines
2016Co-Authors: Damien Lanfray, Helene Castel, Hubert Vaudry, Jérôme Leprince, Sébastien Arthaud, Johanne Ouellet, Vincent Compère, Jean-luc Do Rego, Benjamin Lefranc, Marie-christine TononAbstract:Hypothalamic glucose–sensing is involved in the control of feed-ing behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octade-caneuropeptide (ODN), collectively named Endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of Endozepines in brain glucose–sensing. First, we showed that intracerebroventric-ular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glu-cose stimulates Endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic ef-fect of central administration of glucose was blunted by coinjec-tion of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an OD
-
Gliotransmission and Brain Glucose Sensing Critical Role of Endozepines
2016Co-Authors: Damien Lanfray, Helene Castel, Hubert Vaudry, Jérôme Leprince, Sébastien Arthaud, Johanne Ouellet, Vincent Compère, Jean-luc Do Rego, Benjamin Lefranc, Marie-christine TononAbstract:Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named Endozepines, are secreted by astroglia, and ODN is a potent anorexigenic fac-tor. Therefore, we investigated the involvement of Endozepines in brain glucose sensing. First, we showed that intracerebroven-tricular administration of glucose in rats increases DBI expres-sion in hypothalamic glial-like tanycytes. We then demonstrated that glucose stimulates Endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by a
Jérôme Leprince - One of the best experts on this subject based on the ideXlab platform.
-
Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases.
Frontiers in endocrinology, 2020Co-Authors: Olfa Masmoudi-kouki, Jérôme Leprince, Benjamin Lefranc, Julien Chuquet, Yosra Hamdi, Ikram Ghouili, Seyma Bahdoudi, Amira Namsi, Taoufik Ghrairi, Marie-christine TononAbstract:Octadecaneuropeptide (ODN) and its precursor diazepam-binding inhibitor (DBI) are peptides belonging to the family of Endozepines. Endozepines are exclusively produced by astroglial cells in the central nervous system of mammals, and their release is regulated by stress signals and neuroactive compounds. There is now compelling evidence that the gliopeptide ODN protects cultured neurons and astrocytes from apoptotic cell death induced by various neurotoxic agents. In vivo, ODN causes a very strong neuroprotective action against neuronal degeneration in a mouse model of Parkinson's disease. The neuroprotective activity of ODN is based on its capacity to reduce inflammation, apoptosis, and oxidative stress. The protective effects of ODN are mediated through its metabotropic receptor. This receptor activates a transduction cascade of second messengers to stimulate protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathways, which in turn inhibits the expression of proapoptotic factor Bax and the mitochondrial apoptotic pathway. In N2a cells, ODN also promotes survival and stimulates neurite outgrowth. During the ODN-induced neuronal differentiation process, numerous mitochondria and peroxisomes are identified in the neurites and an increase in the amount of cholesterol and fatty acids is observed. The antiapoptotic and neurotrophic properties of ODN, including its antioxidant, antiapoptotic, and pro-differentiating effects, suggest that this gliopeptide and some of its selective and stable derivatives may have therapeutic value for the treatment of some neurodegenerative diseases.
-
Glial Endozepines and energy balance: Old peptides with new tricks.
Glia, 2020Co-Authors: Bruno Lebrun, Jérôme Leprince, Marie-christine Tonon, Vincent Prévot, Manon Barbot, Jean-denis TroadecAbstract:The contribution of neuroglial interactions to the regulation of energy balance has gained increasing acceptance in recent years. In this context, Endozepines, endogenous analogs of benzodiazepine derived from diazepam-binding inhibitor, are now emerging as major players. Produced by glial cells (astrocytes and tanycytes), Endozepines have been known for two decades to exert potent anorexigenic effects by acting at the hypothalamic level. However, it is only recently that their modes of action, including the mechanisms by which they modulate energy metabolism, have begun to be elucidated. The data available today are abundant, significant, and sometimes contradictory, revealing a much more complex regulation than initially expected. Several mechanisms of action of Endozepines seem to coexist at the central level, particularly in the hypothalamus. The brainstem has also recently emerged as a potential site of action for Endozepines. In addition to their central anorexigenic effects, Endozepines may also display peripheral effects promoting orexigenic actions, adding to their complexity and raising yet more questions. In this review, we attempt to provide an overview of our current knowledge in this rapidly evolving field and to pinpoint questions that remain unanswered.
-
Neuroprotection with the Endozepine Octadecaneuropeptide, ODN.
Current pharmaceutical design, 2019Co-Authors: Olfa Masmoudi-kouki, Helene Castel, Mohamed Amri, Hubert Vaudry, Jérôme Leprince, Yosra Hamdi, Ikram Ghouili, Seyma Bahdoudi, Hadhemi Kaddour, David VaudryAbstract:The term Endozepines designates a family of astroglia-secreted proteins including the diazepambinding inhibitor (DBI) and its processing products, which have been originally isolated and characterized as endogenous ligands of benzodiazepine receptors. It is now clearly established that the octadecaneuropeptide ODN (DBI33-50), acting through the central-type benzodiazepine receptor or a metabotropic receptor, exerts important functions such as proconflict behavior, induction of anxiety, inhibition of pentobarbital-provoked sleep, decrease of water consumption and reduction of food intake. To mediate its effects, ODN regulates both glial cell and neuronal activities by acting on neurosteroid biosynthesis and/or neuropeptide expression. In addition, ODN stimulates astrocyte proliferation and protects both neurons and astrocytes from oxidative stress-induced cell death. The antiapoptotic effect of ODN on neural cells is mediated through activation of the ODN metabotropic receptor positively coupled to PKA, PKC and MAPK/ERK transduction pathways, which ultimately reduces the pro-apoptotic gene Bax and stimulates Bcl-2 expressions, and inhibits intracellular reactive oxygen species accumulation. The imbalance in favor of Bcl2 promotes mitochondria functions and blocks in turn caspases activation while at the same time, ODN also activates the endogenous antioxidant system i.e. glutathione biosynthesis, and expression and activities of antioxidant enzymes. In cultured astrocytes, DBI expression is up-regulated during moderate oxidative stress, and authentic ODN production is increased, suggesting that ODN may act as a paracrine factor protecting neighboring neurons. Taken together, the remarkable effect of ODN on the apoptotic cascade suggests that innovative ODN derivatives could potentially be useful for treatment of cerebral injuries involving oxidative stress and neurodegeneration.
-
Glial Endozepines Inhibit Feeding-Related Autonomic Functions by Acting at the Brainstem Level
Frontiers in Neuroscience, 2017Co-Authors: Florent Guillebaud, Jérôme Leprince, Marie-christine Tonon, Clémence Girardet, Anne Abysique, Stéphanie Gaigé, Rym Barbouche, Jérémy Verneuil, Andre Jean, Michel DallaportaAbstract:Endozepines are endogenous ligands for the benzodiazepine receptors and also target a still unidentified GPCR. The Endozepine octadecaneuropeptide (ODN), an endoproteolytic processing product of the diazepam-binding inhibitor (DBI) was recently shown to be involved in food intake control as an anorexigenic factor through ODN-GPCR signaling and mobilization of the melanocortinergic signaling pathway. Within the hypothalamus, the DBI gene is mainly expressed by non-neuronal cells such as ependymocytes, tanycytes, and protoplasmic astrocytes, at levels depending on the nutritional status. Administration of ODN C-terminal octapeptide (OP) in the arcuate nucleus strongly reduces food intake. Up to now, the relevance of extrahypothalamic targets for Endozepine signaling-mediated anorexia has been largely ignored. We focused our study on the dorsal vagal complex located in the caudal brainstem. This structure is strongly involved in the homeostatic control of food intake and comprises structural similarities with the hypothalamus. In particular, a circumventricular organ, the area postrema (AP) and a tanycyte-like cells forming barrier between the AP and the adjacent nucleus tractus solitarius (NTS) are present. We show here that DBI is highly expressed by ependymocytes lining the fourth ventricle, tanycytes-like cells, as well as by proteoplasmic astrocytes located in the vicinity of AP/NTS interface. ODN staining observed at the electron microscopic level reveals that ODN-expressing tanycyte-like cells and protoplasmic astrocytes are sometimes found in close apposition to neuronal elements such as dendritic profiles or axon terminals. Intracerebroventricular injection of ODN or OP in the fourth ventricle triggers c-Fos activation in the dorsal vagal complex and strongly reduces food intake. We also show that, similarly to leptin, ODN inhibits the swallowing reflex when microinjected into the swallowing pattern generator located in the NTS. In conclusion, we hypothesized that ODN expressing cells located at the AP/NTS interface could release ODN and modify excitability of NTS neurocircuitries involved in food intake control.
-
Gliotransmission and Brain Glucose–Sensing Critical Role of Endozepines
2016Co-Authors: Damien Lanfray, Helene Castel, Hubert Vaudry, Jérôme Leprince, Sébastien Arthaud, Johanne Ouellet, Vincent Compère, Jean-luc Do Rego, Benjamin Lefranc, Marie-christine TononAbstract:Hypothalamic glucose–sensing is involved in the control of feed-ing behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octade-caneuropeptide (ODN), collectively named Endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of Endozepines in brain glucose–sensing. First, we showed that intracerebroventric-ular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glu-cose stimulates Endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic ef-fect of central administration of glucose was blunted by coinjec-tion of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an OD
Pierrick Gandolfo - One of the best experts on this subject based on the ideXlab platform.
-
Increased plasma levels of Endozepines, endogenous ligands of benzodiazepine receptors, during systemic inflammation: a prospective observational study
Critical care (London England), 2014Co-Authors: Thomas Clavier, Pierrick Gandolfo, Marie-christine Tonon, Fabrice Morin, Anne Foutel, Emmanuel Besnier, Antoine Lefevre-scelles, Jean-jacques Tuech, Muriel Quillard, Benoit VeberAbstract:Recent work has shown that benzodiazepines interact with the immune system and exhibit anti-inflammatory effects. By using in vitro models, researchers in several studies have shown that the peptidergic endogenous ligands of benzodiazepine receptors, named Endozepines, are involved in the immune response. All Endozepines identified so far derive from diazepam-binding inhibitor (DBI), which generates several biologically active fragments. The aim of the present study was to measure plasma levels of DBI-like immunoreactivity (DBI-LI) in a rat model of sepsis and in patients with systemic inflammation from septic or non-septic origin. Cecal ligation and puncture (CLP) or sham surgery was performed in rats. Blood samples were taken from animals, patients hospitalized for digestive surgery with inflammatory diseases, and healthy volunteers. Measurements of plasma DBI-related peptides were carried out by radioimmunoassay in animal and human samples. In the rats, CLP provoked an increase of plasma DBI-LI (+37%) 6 hours postsurgery. In humans, DBI-LI levels were significantly higher in the systemic inflammation group than in the healthy volunteer group (48.6 (32.7 to 77.7) pg/ml versus 11.1 (5.9 to 35.3) pg/ml, P
-
Increased plasma levels of Endozepines, endogenous ligands of benzodiazepine receptors, during systemic inflammation: a prospective observational study
Critical Care, 2014Co-Authors: Thomas Clavier, Pierrick Gandolfo, Marie-christine Tonon, Fabrice Morin, Anne Foutel, Emmanuel Besnier, Antoine Lefevre-scelles, Jean-jacques Tuech, Muriel Quillard, Benoit VeberAbstract:Introduction Recent work has shown that benzodiazepines interact with the immune system and exhibit anti-inflammatory effects. By using in vitro models, researchers in several studies have shown that the peptidergic endogenous ligands of benzodiazepine receptors, named Endozepines , are involved in the immune response. All Endozepines identified so far derive from diazepam-binding inhibitor (DBI), which generates several biologically active fragments. The aim of the present study was to measure plasma levels of DBI-like immunoreactivity (DBI-LI) in a rat model of sepsis and in patients with systemic inflammation from septic or non-septic origin. Methods Cecal ligation and puncture (CLP) or sham surgery was performed in rats. Blood samples were taken from animals, patients hospitalized for digestive surgery with inflammatory diseases, and healthy volunteers. Measurements of plasma DBI-related peptides were carried out by radioimmunoassay in animal and human samples. Results In the rats, CLP provoked an increase of plasma DBI-LI (+37%) 6 hours postsurgery. In humans, DBI-LI levels were significantly higher in the systemic inflammation group than in the healthy volunteer group (48.6 (32.7 to 77.7) pg/ml versus 11.1 (5.9 to 35.3) pg/ml, P < 0.001). We found a positive correlation between Endozepine levels and Acute Physiology and Chronic Health Evaluation II score ( r _s = 0.33 (0.026 to 0.58), P
-
Endozepines
2013Co-Authors: Marie-christine Tonon, María M. Malagón, Pierrick Gandolfo, Georges Pelletier, Jérôme Leprince, Fabrice Morin, Vincent Compère, Hubert VaudryAbstract:The existence of specific binding sites for benzodiazepines has led to the discovery of endogenous ligands for benzodiazepine recep-tors that are collectively designated by the term Endozepines. In the brain and in peripheral nervous tissues, Endozepines are exclusively expressed by glial cells. The release of Endozepines from cultured astrocytes is finely regulated by neurotransmitters and neuro-peptides. Endozepines exert their effects either through classical central- and peripheral-type benzodiazepine receptors or through G protein-coupled receptors. Intracerebroventricular injection of Endozepines induces marked effects on anxiety, sleep, and food consumption. The concentration of Endozepines in the brain and cerebrospinal fluid is affected in various diseases including depres-sion, Alzheimer’s disease, and hepatic encephalopathy.
-
Protective effect of the octadecaneuropeptide on hydrogen peroxide-induced oxidative stress and cell death in cultured rat astrocytes
Journal of Neurochemistry, 2011Co-Authors: Yosra Hamdi, Raya Hachem, Pierrick Gandolfo, Jérôme Leprince, Olfa Masmoudi-kouki, David Vaudry, Hadhemi Kaddour, Feten Belhadj, Meherzia Mokni, Hubert VaudryAbstract:Oxidative stress, resulting from accumulation of reactive oxygen species (ROS), plays a critical role on astrocyte death associated with neurodegenerative diseases. Astroglial cells produce Endozepines, a family of biologically active peptides that have been implicated in cell protection. Thus, the purpose of the present study was to investigate the potential protective effect of one of the Endozepines, the octadecaneuropeptide ODN, on hydrogen peroxide (H(2) O(2) )-induced oxidative stress and cell death in rat astrocytes. Incubation of cultured astrocytes with graded concentrations of H(2) O(2) for 1 h provoked a dose-dependent reduction of the number of living cells as evaluated by lactate dehydrogenase assay. The cytotoxic effect of H(2) O(2) was associated with morphological modifications that were characteristic of apoptotic cell death. H(2) O(2) -treated cells exhibited high level of ROS associated with a reduction of both superoxide dismutases (SOD) and catalase activities. Pre-treatment of astrocytes with low concentrations of ODN dose-dependently prevented cell death induced by H(2) O(2) . This effect was accompanied by a marked attenuation of ROS accumulation, reduction of mitochondrial membrane potential and activation of caspase 3 activity. ODN stimulated SOD and catalase activities in a concentration-dependent manner, and blocked H(2) O(2) -evoked inhibition of SOD and catalase activities. Blockers of SOD and catalase suppressed the effect of ODN on cell survival. Taken together, these data demonstrate for the first time that ODN is a potent protective agent that prevents oxidative stress-induced apoptotic cell death.
-
Protective effect of the octadecaneuropeptide on hydrogen peroxide‐induced oxidative stress and cell death in cultured rat astrocytes
Journal of neurochemistry, 2011Co-Authors: Yosra Hamdi, Raya Hachem, Pierrick Gandolfo, Jérôme Leprince, Olfa Masmoudi-kouki, David Vaudry, Hadhemi Kaddour, Feten Belhadj, Meherzia Mokni, Hubert VaudryAbstract:J. Neurochem. (2011) 118, 416–428. Abstract Oxidative stress, resulting from accumulation of reactive oxygen species (ROS), plays a critical role on astrocyte death associated with neurodegenerative diseases. Astroglial cells produce Endozepines, a family of biologically active peptides that have been implicated in cell protection. Thus, the purpose of the present study was to investigate the potential protective effect of one of the Endozepines, the octadecaneuropeptide ODN, on hydrogen peroxide (H2O2)-induced oxidative stress and cell death in rat astrocytes. Incubation of cultured astrocytes with graded concentrations of H2O2 for 1 h provoked a dose-dependent reduction of the number of living cells as evaluated by lactate dehydrogenase assay. The cytotoxic effect of H2O2 was associated with morphological modifications that were characteristic of apoptotic cell death. H2O2-treated cells exhibited high level of ROS associated with a reduction of both superoxide dismutases (SOD) and catalase activities. Pre-treatment of astrocytes with low concentrations of ODN dose-dependently prevented cell death induced by H2O2. This effect was accompanied by a marked attenuation of ROS accumulation, reduction of mitochondrial membrane potential and activation of caspase 3 activity. ODN stimulated SOD and catalase activities in a concentration-dependent manner, and blocked H2O2-evoked inhibition of SOD and catalase activities. Blockers of SOD and catalase suppressed the effect of ODN on cell survival. Taken together, these data demonstrate for the first time that ODN is a potent protective agent that prevents oxidative stress-induced apoptotic cell death.
E Lugaresi - One of the best experts on this subject based on the ideXlab platform.
-
Endozepines in recurrent stupor
Sleep Medicine Reviews, 2005Co-Authors: Pietro Cortelli, E Lugaresi, P Tinuper, Rossella Avallone, Mario Baraldi, M.l. Zeneroli, Jessica Mandrioli, Lorenzo Corsi, Roberto Riva, Agostino BaruzziAbstract:Summary Stupor is a condition from which the subject can be aroused only by vigorous stimuli. Most patients with stupor have a diffuse organic cerebral dysfunction. Rarely stupor is recurrent and no specific causes can be found. Patients with idiopathic recurrent stupor were awakened by i.v. administration of an antagonist (flumazenil) of the benzodiazepine recognition site located in the GABA A receptor. Since no exogenous benzodiazepines were detected in plasma and cerebrospinal fluid by high performance liquid chromatography, an excess of endogenous benzodiazepine-like compounds (Endozepines) was proposed as the cause of stupor. The existence of Endozepines, their widespread distribution in the CNS and their involvement in hepatic encephalopathy are established. However, the origin of these compounds, how biosynthesis occurs and the mechanisms and causes through which they alter brain functions are poorly understood. The fact that a number of synthetic benzodiazepines are difficult to detect using conventional techniques and the discovery that some cases of recurrent stupor were caused by fraudulent administration of lorazepam question whether the concept of Endozepine recurrent stupor can be sustained. This review summarizes the state of Endozepine physiology and pharmacology and the clinical syndromes attributed to their involvement. A diagnostic work-up to define Endozepine-induced recurrent stupor is suggested.
-
suspected covert lorazepam administration misdiagnosed as recurrent Endozepine stupor
Brain, 1998Co-Authors: E Lugaresi, P Tinuper, Giuseppe Plazzi, Pasquale Montagna, R GallassiAbstract:Istituto di Clinica Neurologica dell’Universita`di Bologna, Bologna, ItalyCorrespondence to: Professor Elio Lugaresi, Clinica Neurologica, Via Ugo Foscolo 7, 40123 Bologna, ItalyWe recently reported in Brain (Lugaresi et al., 1998) 20cases of idiopathic recurrent stupor due to Endozepine-4accumulation in the blood. Samples obtained from nine ofthese patients were analysed by gas chromatography–massspectrometry to rule out contaminating synthetic benzo-diazepines (Rothstein et al., 1992). All these samplescontained Endozepine-4 concentrations high enough toaccount for the stuporous state of the patients. The other 11cases of idiopathic recurring stupor were diagnosed on thebasis of clinical criteria alone since they were identical tothe patients with documented Endozepine-4 accumulation.All presented the same clinical picture and EEG pattern (lowamplitude, unreactive, background activity) during stuporand a reversal of the stuporous state after flumazeniladministration (awakening and EEG normalization). Again,toxicological immunoenzymatic tests failed to detect eventraces of synthetic benzodiazepines.We subsequently investigated a cluster of nine patientspresenting recurrent stuporous attacks with almostsimultaneous onset which had occurred in a restricted ruralarea near Lucca in Tuscany. Except for the extraordinaryclustering in time and space, these patients were in allrespects similar to the sporadic idiopathic recurring stuporpatients previously encountered by us. The stuporous episodesin fact lasted 1–2 days and were followed by confusion andamnesia; ictal EEG was characterized by the typical lowvoltage, 13–14 Hz background activity, and flumazeniladministration led to transient awakening and EEGnormalization. Routine toxicological immunoenzymatic assayhad ruled out the presence of benzodiazepines.However, in the meantime, a newer more specific toxico-logical assay, liquid chromatography–mass spectrometry, hadbecome available to us. Because of the unusual epidemiology,we used this technique to re-analyse blood samples from theTuscan patients. This time we detected in the blood of all ofthese patients the benzodiazepine lorazepam which had not© Oxford University Press 1998been disclosed when we had used gas chromatography–massspectrometry analysis. We could therefore deduce a fraudulentlorazepam intoxication in these patients, and exclude anendogenous benzodiazepine (Endozepine) origin of the stupor.Besides highlighting the difficulties inherent to theascertainment of surreptitious benzodiazepine administration,we wish here to offer also the following conclusions:(i) Toxicological immunoenzyme assays for benzo-diazepines currently implemented by the hospital emergencyservices, though they may reveal diazepam and otherbenzodiazepines, may prove negative if the drug present inthe blood is lorazepam.(ii) Biological tests on the chromatographic fractioncontaining Endozepine-4 do not rule out that the episodes ofrecurrent stupor are due to lorazepam intoxication sincelorazepam migrates in the same chromatographic fraction asEndozepine during high performance liquid chromatography.(iii) The agent responsible for recurrent stuporous attackscan only be identified by means of liquid chromatography–mass spectrometry.Finally, in the light of the above findings, the Endozepineorigin of the stuporous episodes in the patients we recentlyreported in Brain (Lugaresi et al., 1998), especially in thosewho did not undergo gas chromatography–mass spectrometry,should be considered as still unproven.
-
Endozepine stupor. Recurring stupor linked to Endozepine-4 accumulation.
Brain : a journal of neurology, 1998Co-Authors: E Lugaresi, P Montagna, P Tinuper, G Plazzi, R Gallassi, T C Wang, S P Markey, J D RothsteinAbstract:Recurring stupor can be caused by repeated metabolic, toxic or structural brain disturbances. Recently, cases of recurring stupor, with fast EEG activity were shown to display increased endogenous benzodiazepine-like activity during the episodes of stupor. Patients with recurring stupor underwent extensive metabolic and toxicologic screening, EEG and brain imaging. Endozepines and exogenously administered benzodiazepines were assayed in plasma and CSF by means of mass spectrometry. Flumazenil, a benzodiazepine antagonist was administered and the behavioural and EEG responses monitored. Treatment with oral flumazenil was attempted in selected cases. Twenty patients were found with recurring stupor. Episodes had begun between ages 18 and 67 years, and in nine patients, had disappeared spontaneously after 4-6 years with symptoms. Stupor lasted hours or days. Onset of the episodes and frequency were unpredictable. Patients were normal between attacks. Stupor was characterized by initial drowsiness, staggering and behavioural changes, followed by deep sleep and spontaneous recovery with post-ictal amnesia. Biochemical screening and brain imaging were always normal. Ictal EEG showed fast background activity, and flumazenil transiently awoke the patients and normalized the EEG. In the nine cases examined, Endozepine-4 levels were increased during the stupor. Oral flumazenil reduced the frequency of the attacks in three of these nine patients. Recurring episodes of stupor may be due to increased Endozepine-4. We propose the term 'Endozepine stupor' for such episodes. Endozepine-4 is an endogenous ligand for the benzodiazepine recognition site at the GABAA receptor, with unknown molecular structure.
-
Endozepine stupor in children
Cephalalgia, 1997Co-Authors: S. Soriani, E Lugaresi, P Tinuper, Giuseppe Plazzi, M Carrozzi, L. De Carlo, Federica Provini, Jeffrey D. Rothstein, F Bouquet, Pasquale MontagnaAbstract:Recurring episodes of stupor in adults have been shown to be related to increased levels of Endozepines, which are endogenous ligands for the GABAA receptors. We report here two children presenting with recurrent episodes of stupor associated with fast EEG activity who had increased levels of Endozepine-4 in plasma. Mass spectroscopy did not reveal commercially available benzodiazepines. Interictal Endozepine-4 levels were normal. In one of the patients, administration of flumazenil (0.25 mg i.v.), a benzodiazepine inverse agonist, induced improvement of consciousness and attenuation of EEG fast activity. In conclusion, children presenting with recurrent episodes of stupor and EEG fast activity should be evaluated for Endozepine levels and can be effectively treated with i.v. flumazenil.
-
Plasma endogenous benzodiazepine-like activity in sleep disorders with excessive daytime sleepiness
Neurology, 1995Co-Authors: Pasquale Montagna, P Tinuper, Pietro Cortelli, Giuseppe Plazzi, Federica Provini, Jeffrey D. Rothstein, P. Schoch, E Sforza, E LugaresiAbstract:Endozepines are nonhalogenated, benzodiazepine-like, nonpeptide allosteric modulators of the GABAA receptor that mimic the pharmacologic activity of exogenous benzodiazepines and are present in physiologically significant amounts in the brain. [1,2] Increased Endozepine-4 activity is present in idiopathic recurring stupor (IRS), a condition characterized by bouts of stupor and coma reversed by flumazenil, a benzodiazepine antagonist. [3-5] Endozepines could thus have a role in altered mental states characterized by impaired vigilance. Narcolepsy and obstructive sleep apnea syndrome (OSAS) are sleep disorders with excessive daytime somnolence. There are no studies of Endozepine activity in these clinical conditions. We studied 11 drug-free patients with narcolepsy (mean age, 35.9 plus minus 16 years) and nine patients with OSAS (mean age, 51.8 plus minus 11 …