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Journal ArticleDOI

NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders

01 Sep 2017-Trends in Neurosciences (Elsevier)-Vol. 40, Iss: 9, pp 536-554
TL;DR: The diuretic highly specific NKCC1 chloride importer antagonist bumetanide efficiently restores low (Cl-)I levels and attenuates many disorders in experimental conditions and in some clinical trials.
About: This article is published in Trends in Neurosciences.The article was published on 2017-09-01. It has received 156 citations till now. The article focuses on the topics: Bumetanide.
Citations
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Journal ArticleDOI
TL;DR: Recent advances in understanding how loss of MeCP2 impacts different stages of brain development are reviewed, recent findings demonstrating the molecular role ofMeCP2 as a transcriptional repressor are discussed, and primary and secondary effects of Me CP2 loss are assessed.
Abstract: Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into RTT have greatly advanced our understanding of the function and regulation of the multifunctional protein MeCP2. Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms. These factors present challenges to the search for mechanism-based therapeutics for RTT and suggest specific approaches that may be more effective than others.

156 citations

Journal ArticleDOI
TL;DR: The molecular mechanisms of important SLC transporter-mediated physiological processes and their potentials as drug targets are understood in regulating physiology, nutrient sensing and uptake, and risk of diseases.
Abstract: The prevalence of metabolic diseases is growing worldwide. Accumulating evidence suggests that solute carrier (SLC) transporters contribute to the etiology of various metabolic diseases. Consistent with metabolic characteristics, the top five organs in which SLC transporters are highly expressed are the kidney, brain, liver, gut, and heart. We aim to understand the molecular mechanisms of important SLC transporter-mediated physiological processes and their potentials as drug targets. SLC transporters serve as 'metabolic gate' of cells and mediate the transport of a wide range of essential nutrients and metabolites such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. Gene-modified animal models have demonstrated that SLC transporters participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, tissue development, oxidative stress, host defense, and neurological regulation. Furthermore, the human genomic studies have identified that SLC transporters are susceptible or causative genes in various diseases like cancer, metabolic disease, cardiovascular disease, immunological disorders, and neurological dysfunction. Importantly, a number of SLC transporters have been successfully targeted for drug developments. This review will focus on the current understanding of SLCs in regulating physiology, nutrient sensing and uptake, and risk of diseases.

136 citations


Cites background from "NKCC1 Chloride Importer Antagonists..."

  • ...Selective NKCC1 inhibitors known as diuretics including bumetanide and furosemide improve neurological behavior control and lower anxiety, neuropathic pain, and schizophrenia in animals and patients (Ben-Ari, 2017)....

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Journal ArticleDOI
TL;DR: Current knowledge on chloride transporter expression and activity regulation is reviewed and the intriguing potential for existing and future interventions to support chloride homeostasis across a wide range of mental disorders and neurological conditions is highlighted.

93 citations


Cites background from "NKCC1 Chloride Importer Antagonists..."

  • ...These outcomes have been debated and it was argued that bumetanide had not been used as a primary agent to treat the neonatal seizures and that the effect of bumetanide as monotherapy for seizure reduction had not been tested (Ben-Ari, 2017; Pressler et al., 2015)....

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  • ...This notion has evoked studies into the application of bumetanide to this group of patients (Ben-Ari, 2017)....

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  • ...However, in certain pathophysiological conditions fine-tuning of [Cl-]i can become dysregulated and affect GABAergic inhibition (Ben-Ari, 2017)....

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Journal ArticleDOI
TL;DR: The generation of a robust high-throughput drug screening platform that allows for the rapid assessment of KCC2 gene expression in genome-edited human reporter neurons is reported, and a group of compounds that enhance K CC2 expression are identified termed KCC1 expression–enhancing compounds (KEECs).
Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K+/Cl− cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT. To develop neuron-based high-throughput screening (HTS) assays to identify chemical compounds that enhance the expression of the KCC2 gene, we report the generation of a robust high-throughput drug screening platform that allows for the rapid assessment of KCC2 gene expression in genome-edited human reporter neurons. From an unbiased screen of more than 900 small-molecule chemicals, we have identified a group of compounds that enhance KCC2 expression termed KCC2 expression–enhancing compounds (KEECs). The identified KEECs include U.S. Food and Drug Administration–approved drugs that are inhibitors of the fms-like tyrosine kinase 3 (FLT3) or glycogen synthase kinase 3β (GSK3β) pathways and activators of the sirtuin 1 (SIRT1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) pathways. Treatment with hit compounds increased KCC2 expression in human wild-type (WT) and isogenic MECP2 mutant RTT neurons, and rescued electrophysiological and morphological abnormalities of RTT neurons. Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.

85 citations


Cites background from "NKCC1 Chloride Importer Antagonists..."

  • ...Because of the lack of pharmaceutical reagents that enhance KCC2 expression, bumetanide, a blocker of the inward chloride transporter NKCC1 that counteracts KCC2, has been used as an alternative (74)....

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Journal ArticleDOI
TL;DR: This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit and reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents are being activity investigated but have limited published evidence.
Abstract: Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.

72 citations


Cites background from "NKCC1 Chloride Importer Antagonists..."

  • ...2 Bumetanide The diuretic bumetanide, a chlorideimporter antagonist, targets abnormalities in intracellular GABAA chloride levels [56]....

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  • ...It is believed that some children with ASD have a failure in this developmental change in KCC2 expression resulting in GABAA remaining excitatory [56]....

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References
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Journal ArticleDOI
21 Jan 1999-Nature
TL;DR: It is shown that, in pyramidal neurons of the rat hippocampus, the ontogenetic change in GABAA-mediated responses from depolarizing to hyperpolarizing is coupled to a developmental induction of the expression of the neuronal Cl−-extruding K+/Cl − co-transporter, KCC2 (ref. 7).
Abstract: GABA (gamma-aminobutyric acid) is the main inhibitory transmitter in the adult brain, and it exerts its fast hyperpolarizing effect through activation of anion (predominantly Cl-)-permeant GABA(A) receptors. However, during early neuronal development, GABA(A)-receptor-mediated responses are often depolarizing, which may be a key factor in the control of several Ca2+-dependent developmental phenomena, including neuronal proliferation, migration and targeting. To date, however, the molecular mechanism underlying this shift in neuronal electrophysiological phenotype is unknown. Here we show that, in pyramidal neurons of the rat hippocampus, the ontogenetic change in GABA(A)-mediated responses from depolarizing to hyperpolarizing is coupled to a developmental induction of the expression of the neuronal (Cl-)-extruding K+/Cl- co-transporter, KCC2. Antisense oligonucleotide inhibition of KCC2 expression produces a marked positive shift in the reversal potential of GABAA responses in functionally mature hippocampal pyramidal neurons. These data support the conclusion that KCC2 is the main Cl- extruder to promote fast hyperpolarizing postsynaptic inhibition in the brain.

2,045 citations


"NKCC1 Chloride Importer Antagonists..." refers background in this paper

  • ...The developmental reduction of (Cl )I levels is mediated primarily by two chloride cotransporters – the NKCC1 importer (Box 1) and the KCC2 chloride exporter [1,4,5]....

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Journal ArticleDOI
TL;DR: The overlapping delay before symptom onset in humans and mice raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2, and generates mice lacking Mecp2 using Cre-loxP technology.
Abstract: Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

1,480 citations


"NKCC1 Chloride Importer Antagonists..." refers background in this paper

  • ...Deficits in KCC2 have been observed in human transformed progenitor cells from RTT patients [84], suggesting that the delayed expression of KCC2 during development might explain the late manifestations of RTT....

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  • ...Mecp2 also regulates the timing of critical period of visual plasticity with an important role of paravalbumin interneurons, stressing the importance of GABA signaling and developmental processes in RTT [82]....

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  • ...Knocking out Mecp2 selectively from GABAergic interneurons recapitulates some of RTT features [74,76,77]....

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  • ...Rett Syndrome (RTT)...

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  • ...Different symptoms of RTT may manifest through specific loss of Mecp2 in different brain regions that are also associated with an excitatory/inhibitory imbalance [73,74]....

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Journal ArticleDOI
TL;DR: In neurones in which evoked GDPs were blocked by bicuculline, a NMDA‐mediated component was revealed by increasing the strength or the frequency of stimulation, and during the second week of postnatal life, superfusion with bicuciulline induced, as in adult slices, interictal discharges.
Abstract: 1. Intracellular recordings were made from rat CA3 hippocampal neurones in vitro during the first eighteen days of postnatal life. The cells had resting membrane potentials more negative than -51 mV, action potentials greater than 55 mV and membrane input resistances of 117 +/- 12 M omega. An unusual characteristic of these cells was the presence of spontaneous giant depolarizing potentials (GDPs) which were observed during the first eight postnatal (P) days in over 85% of neurones. They were less frequent between P9 and P12 (48%) and disappeared after P12. 2. The GDPs were synchronously generated by a population of neurones; they reversed polarity at -27 mV when recorded with KCl-containing electrodes and at -51 mV with potassium acetate- or potassium methylsulphate-filled electrodes. 3. The GDPs were blocked by bath application of bicuculline (10 microM) or picrotoxin (100-200 microM). Exogenously applied gamma-aminobutyric acid (GABA; 0.2-1 mM) induced at resting membrane potential a bicuculline-sensitive membrane depolarization which reversed polarity at -25 and -51 mV when recorded with KCl- or potassium methylsulphate-filled electrodes respectively. 4. The GDPs were reduced in frequency or blocked by the N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-7-phosphonoheptanoate (AP-7; 50 microM), D(-)2-amino-5-phosphonovalerate (AP-5, 10-50 microM) and (+-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10-50 microM) or NMDA channel blockers phencyclidine (2 microM) and ketamine (20 microM). 5. Stimulation of the hilus during the first week of life evoked a GDP followed by a hyperpolarization. The GDPs were generated by a population of synchronized neurones and reversed polarity at -27 mV with KCl-filled electrodes and at -52 mV with potassium acetate- or potassium methylsulphate-containing electrodes. 6. Bath application of bicuculline (1-10 microM) or picrotoxin (100-200 microM) reversibly blocked the evoked GDPs in the majority of cells. The NMDA receptor antagonists AP-5 (50 microM), AP-7 (50 microM) and CPP (30 microM) usually reduced the amplitude and the duration of the evoked GDPs. In neurones in which evoked GDPs were blocked by bicuculline, a NMDA-mediated component was revealed by increasing the strength or the frequency of stimulation. 7. During the second week of postnatal life, when spontaneous GDPs were extremely rare or absent, superfusion with bicuculline (10 microM) induced, as in adult slices, interictal discharges. These reversed polarity near 0 mV with KCl- or potassium acetate-containing electrodes and were reduced in amplitude and duration by AP-5 (50 microM).(ABSTRACT TRUNCATED AT 400 WORDS)

1,283 citations

Journal ArticleDOI
TL;DR: Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.
Abstract: Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100–150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of austism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.

1,252 citations


"NKCC1 Chloride Importer Antagonists..." refers background in this paper

  • ...Administration of the antiepileptic agent valproic acid (VPA) during gestation augments the incidence of ASD in humans [49]....

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  • ...Discovered two decades ago, the intrauterine valproate model is one the most investigated animal model of ASD, as VPA mimics autistic features and developmental disorders in many animal species [49]....

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Journal ArticleDOI
TL;DR: The results indicate that the role of MECp2 is not restricted to the immature brain, but becomes critical in mature neurons, and that Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.
Abstract: Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.

1,233 citations


"NKCC1 Chloride Importer Antagonists..." refers background in this paper

  • ...Different symptoms of RTT may manifest through specific loss of Mecp2 in different brain regions that are also associated with an excitatory/inhibitory imbalance [73,74]....

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