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Laurent Vinay - One of the best experts on this subject based on the ideXlab platform.
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prochlorperazine increases kcc2 function and reduces spasticity after spinal cord injury
Journal of Neurotrauma, 2017Co-Authors: Sylvie Liabeuf, Laetitia Stuhlgourmand, Florian Gackiere, Renzo Mancuso, Irene Sanchez Brualla, Philippe Marino, Frederic Brocard, Laurent VinayAbstract:Abstract In mature neurons, low intracellular Chloride level required for inhibition is maintained by the Potassium-Chloride Cotransporter, KCC2. Impairment of Cl− extrusion after KCC2 dysfunction has been involved in many central nervous system disorders, such as seizures, neuropathic pain, or spasticity, after a spinal cord injury (SCI). This makes KCC2 an appealing drug target for restoring Cl− homeostasis and inhibition in pathological conditions. In the present study, we screen the Prestwick Chemical Library® and identify conventional antipsychotics phenothiazine derivatives as enhancers of KCC2 activity. Among them, prochlorperazine hyperpolarizes the Cl− equilibrium potential in motoneurons of neonatal rats and restores the reciprocal inhibition post-SCI. The compound alleviates spasticity in chronic adult SCI rats with an efficacy equivalent to the antispastic agent, baclofen, and rescues the SCI-induced downregulation of KCC2 in motoneurons below the lesion. These pre-clinical data support prochl...
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activation of 5 ht2a receptors upregulates the function of the neuronal k cl Cotransporter kcc2
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Remi Bos, Sylvie Liabeuf, Cecile Brocard, Pascale Boulenguez, Helene Bras, Karina Sadlaoud, Dorothee Buttigieg, Georg Haase, Laurent VinayAbstract:In healthy adults, activation of γ-aminobutyric acid (GABA)A and glycine receptors inhibits neurons as a result of low intracellular Chloride concentration ([Cl–]i), which is maintained by the Potassium-Chloride Cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), EIPSP, in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered Chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT2AR agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).
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developmental up regulation of the Potassium Chloride Cotransporter type 2 in the rat lumbar spinal cord
Neuroscience, 2009Co-Authors: Aurelie Stil, Sylvie Liabeuf, Celine Jeanxavier, Cecile Brocard, Jeancharles Viemari, Laurent VinayAbstract:Abstract The classical GABA/glycine hyperpolarizing inhibition is not observed in the immature spinal cord. GABA A and glycine receptors are anions channels and the efficacy of inhibitory transmission in the spinal cord is largely determined by the gradient between intracellular and extracellular Chloride concentrations. The concentration of intracellular Chloride in neurons is mainly regulated by two cation–Chloride Cotransporters, the Potassium–Chloride Cotransporter 2 (KCC2) and the sodium–Potassium–Chloride co-transporter 1 (NKCC1). In this study, we measured the reversal potential of IPSPs (E IPSP ) of lumbar motoneurons during the first postnatal week and we investigated the expression of KCC2 and NKCC1 in the ventral horn of the spinal cord from the embryonic day 17 to the postnatal day 20 in the rat. Our results suggest that the negative shift of E IPSP from above to below the resting membrane potential occurs during the first postnatal week when the expression of KCC2 increases significantly and the expression of NKCC1 decreases. KCC2 immunolabeling surrounded motoneurons, presumably in the plasma membrane and NKCC1 immunolabeling appeared outside this KCC2-labeled fine strip. Taken together, the present results indicate that maturation of Chloride homeostasis is not completed at birth in the rat and that the upregulation of KCC2 plays a key role in the shift from depolarizing to hyperpolarizing IPSPs.
Sylvie Liabeuf - One of the best experts on this subject based on the ideXlab platform.
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prochlorperazine increases kcc2 function and reduces spasticity after spinal cord injury
Journal of Neurotrauma, 2017Co-Authors: Sylvie Liabeuf, Laetitia Stuhlgourmand, Florian Gackiere, Renzo Mancuso, Irene Sanchez Brualla, Philippe Marino, Frederic Brocard, Laurent VinayAbstract:Abstract In mature neurons, low intracellular Chloride level required for inhibition is maintained by the Potassium-Chloride Cotransporter, KCC2. Impairment of Cl− extrusion after KCC2 dysfunction has been involved in many central nervous system disorders, such as seizures, neuropathic pain, or spasticity, after a spinal cord injury (SCI). This makes KCC2 an appealing drug target for restoring Cl− homeostasis and inhibition in pathological conditions. In the present study, we screen the Prestwick Chemical Library® and identify conventional antipsychotics phenothiazine derivatives as enhancers of KCC2 activity. Among them, prochlorperazine hyperpolarizes the Cl− equilibrium potential in motoneurons of neonatal rats and restores the reciprocal inhibition post-SCI. The compound alleviates spasticity in chronic adult SCI rats with an efficacy equivalent to the antispastic agent, baclofen, and rescues the SCI-induced downregulation of KCC2 in motoneurons below the lesion. These pre-clinical data support prochl...
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activation of 5 ht2a receptors upregulates the function of the neuronal k cl Cotransporter kcc2
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Remi Bos, Sylvie Liabeuf, Cecile Brocard, Pascale Boulenguez, Helene Bras, Karina Sadlaoud, Dorothee Buttigieg, Georg Haase, Laurent VinayAbstract:In healthy adults, activation of γ-aminobutyric acid (GABA)A and glycine receptors inhibits neurons as a result of low intracellular Chloride concentration ([Cl–]i), which is maintained by the Potassium-Chloride Cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), EIPSP, in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered Chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT2AR agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).
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down regulation of the Potassium Chloride Cotransporter kcc2 contributes to spasticity after spinal cord injury
Nature Medicine, 2010Co-Authors: Pascale Boulenguez, Aurelie Stil, Sylvie Liabeuf, Celine Jeanxavier, Cecile Brocard, Remi Bos, Helene Bras, Pascal DarbonAbstract:Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABAA) and glycine receptors inhibits neurons as a result of low intracellular Chloride (Cl-) concentration, which is maintained by the Potassium-Chloride Cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl- equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.
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developmental up regulation of the Potassium Chloride Cotransporter type 2 in the rat lumbar spinal cord
Neuroscience, 2009Co-Authors: Aurelie Stil, Sylvie Liabeuf, Celine Jeanxavier, Cecile Brocard, Jeancharles Viemari, Laurent VinayAbstract:Abstract The classical GABA/glycine hyperpolarizing inhibition is not observed in the immature spinal cord. GABA A and glycine receptors are anions channels and the efficacy of inhibitory transmission in the spinal cord is largely determined by the gradient between intracellular and extracellular Chloride concentrations. The concentration of intracellular Chloride in neurons is mainly regulated by two cation–Chloride Cotransporters, the Potassium–Chloride Cotransporter 2 (KCC2) and the sodium–Potassium–Chloride co-transporter 1 (NKCC1). In this study, we measured the reversal potential of IPSPs (E IPSP ) of lumbar motoneurons during the first postnatal week and we investigated the expression of KCC2 and NKCC1 in the ventral horn of the spinal cord from the embryonic day 17 to the postnatal day 20 in the rat. Our results suggest that the negative shift of E IPSP from above to below the resting membrane potential occurs during the first postnatal week when the expression of KCC2 increases significantly and the expression of NKCC1 decreases. KCC2 immunolabeling surrounded motoneurons, presumably in the plasma membrane and NKCC1 immunolabeling appeared outside this KCC2-labeled fine strip. Taken together, the present results indicate that maturation of Chloride homeostasis is not completed at birth in the rat and that the upregulation of KCC2 plays a key role in the shift from depolarizing to hyperpolarizing IPSPs.
Cecile Brocard - One of the best experts on this subject based on the ideXlab platform.
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activation of 5 ht2a receptors upregulates the function of the neuronal k cl Cotransporter kcc2
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Remi Bos, Sylvie Liabeuf, Cecile Brocard, Pascale Boulenguez, Helene Bras, Karina Sadlaoud, Dorothee Buttigieg, Georg Haase, Laurent VinayAbstract:In healthy adults, activation of γ-aminobutyric acid (GABA)A and glycine receptors inhibits neurons as a result of low intracellular Chloride concentration ([Cl–]i), which is maintained by the Potassium-Chloride Cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), EIPSP, in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered Chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT2AR agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).
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down regulation of the Potassium Chloride Cotransporter kcc2 contributes to spasticity after spinal cord injury
Nature Medicine, 2010Co-Authors: Pascale Boulenguez, Aurelie Stil, Sylvie Liabeuf, Celine Jeanxavier, Cecile Brocard, Remi Bos, Helene Bras, Pascal DarbonAbstract:Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABAA) and glycine receptors inhibits neurons as a result of low intracellular Chloride (Cl-) concentration, which is maintained by the Potassium-Chloride Cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl- equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.
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developmental up regulation of the Potassium Chloride Cotransporter type 2 in the rat lumbar spinal cord
Neuroscience, 2009Co-Authors: Aurelie Stil, Sylvie Liabeuf, Celine Jeanxavier, Cecile Brocard, Jeancharles Viemari, Laurent VinayAbstract:Abstract The classical GABA/glycine hyperpolarizing inhibition is not observed in the immature spinal cord. GABA A and glycine receptors are anions channels and the efficacy of inhibitory transmission in the spinal cord is largely determined by the gradient between intracellular and extracellular Chloride concentrations. The concentration of intracellular Chloride in neurons is mainly regulated by two cation–Chloride Cotransporters, the Potassium–Chloride Cotransporter 2 (KCC2) and the sodium–Potassium–Chloride co-transporter 1 (NKCC1). In this study, we measured the reversal potential of IPSPs (E IPSP ) of lumbar motoneurons during the first postnatal week and we investigated the expression of KCC2 and NKCC1 in the ventral horn of the spinal cord from the embryonic day 17 to the postnatal day 20 in the rat. Our results suggest that the negative shift of E IPSP from above to below the resting membrane potential occurs during the first postnatal week when the expression of KCC2 increases significantly and the expression of NKCC1 decreases. KCC2 immunolabeling surrounded motoneurons, presumably in the plasma membrane and NKCC1 immunolabeling appeared outside this KCC2-labeled fine strip. Taken together, the present results indicate that maturation of Chloride homeostasis is not completed at birth in the rat and that the upregulation of KCC2 plays a key role in the shift from depolarizing to hyperpolarizing IPSPs.
Harald Sontheimer - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the sodium Potassium Chloride Cotransporter isoform 1 reduces glioma invasion
Cancer Research, 2010Co-Authors: Brian R Haas, Harald SontheimerAbstract:Malignant gliomas metastasize throughout the brain by infiltrative cell migration into peritumoral areas. Invading cells undergo profound changes in cell shape and volume as they navigate extracellular spaces along blood vessels and white matter tracts. Volume changes are aided by the concerted release of osmotically active ions, most notably K+ and Cl−. Their efflux through ion channels along with obligated water causes rapid cell shrinkage. Suitable ionic gradients must be established and maintained through the activity of ion transport systems. Here, we show that the Sodium-Potassium-Chloride Cotransporter Isoform-1 (NKCC1) provides the major pathway for Cl− accumulation in glioma cells. NKCC1 localizes to the leading edge of invading processes, and pharmacologic inhibition using the loop diuretic bumetanide inhibits in vitro Transwell migration by 25% to 50%. Short hairpin RNA knockdowns of NKCC1 yielded a similar inhibition and a loss of bumetanide-sensitive cell volume regulation. A loss of NKCC1 function did not affect cell motility in two-dimensional assays lacking spatial constraints but manifested only when cells had to undergo volume changes during migration. Intracranial implantation of human gliomas into severe combined immunodeficient mice showed a marked reduction in cell invasion when NKCC1 function was disrupted genetically or by twice daily injection of the Food and Drug Administration–approved NKCC1 inhibitor Bumex. These data support the consideration of Bumex as adjuvant therapy for patients with high-grade gliomas. Cancer Res; 70(13); 5597–606. ©2010 AACR.
Clifford J Woolf - One of the best experts on this subject based on the ideXlab platform.
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therapeutic restoration of spinal inhibition via druggable enhancement of Potassium Chloride Cotransporter kcc2 mediated Chloride extrusion in peripheral neuropathic pain
JAMA Neurology, 2014Co-Authors: Kristopher T Kahle, Arjun Khanna, David E Clapham, Clifford J WoolfAbstract:Peripheral neuropathic pain, typified by the development of spontaneous pain or pain hypersensitivity following injury to the peripheral nervous system, is common, greatly impairs quality of life, and is inadequately treated with available drugs. Maladaptive changes in Chloride homeostasis due to a decrease in the functional expression of the Potassium-Chloride Cotransporter KCC2 in spinal cord dorsal horn neurons are a major contributor to the central disinhibition of γ-aminobutyric acid type A receptor– and glycine receptor–mediated signaling that characterizes neuropathic pain. A compelling novel analgesic strategy is to restore spinal ionotropic inhibition by enhancing KCC2-mediated Chloride extrusion. We review the data on which this theory of alternative analgesia is based, discuss recent high-throughput screens that have searched for small-molecule activators of KCC2, and propose other strategies of KCC2 activation based on recent developments in the basic understanding of KCC2’s functional regulation. Exploiting the Chloride-dependent functional plasticity of the γ-aminobutyric acid and glycinergic system by targeting KCC2 may be a tenable method of restoring ionotropic inhibition not only in neuropathic pain but also in other “hyperexcitable” diseases of the nervous system such as seizures and spasticity.