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1.
Br J Pharmacol ; 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38922847

RESUMEN

BACKGROUND AND PURPOSE: Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs. EXPERIMENTAL APPROACH: We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild-type mice. KEY RESULTS: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. CONCLUSIONS AND IMPLICATIONS: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies.

2.
Elife ; 112022 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-35234610

RESUMEN

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.


Asunto(s)
Epilepsia , Canal de Sodio Activado por Voltaje NAV1.6 , Animales , Mutación con Ganancia de Función , Ratones , Mutación , Canal de Sodio Activado por Voltaje NAV1.6/genética , Neuronas/fisiología , Ratas , Sodio , Bloqueadores de los Canales de Sodio/farmacología
3.
Bioorg Med Chem Lett ; 45: 128133, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34044121

RESUMEN

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of NaV1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide NaV inhibitors that bind to the channel voltage sensors, these NaV1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.


Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Sulfonamidas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química
4.
Cell Rep ; 27(6): 1769-1780.e4, 2019 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-31067462

RESUMEN

The sterile alpha motif (SAM) and SRC homology 3 (SH3) domain containing protein 1 (Sash1) acts as a scaffold in TLR4 signaling. We generated Sash1-/- mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a delay in maturation of alveolar epithelial cells causing reduced surfactant-associated protein synthesis. We show that Sash1 interacts with ß-arrestin 1 downstream of the TLR4 pathway to activate Akt and endothelial nitric oxide synthase (eNOS) in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells affects alveolar epithelial cells in a cGMP-dependent manner, inducing maturation of alveolar type 1 and 2 cells. Thus, we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 regulates alveolar epithelial cell maturation and promotes pulmonary surfactant production through nitric oxide signaling. Lung immaturity is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy.


Asunto(s)
Células Endoteliales/metabolismo , Pulmón/crecimiento & desarrollo , Óxido Nítrico/metabolismo , Transducción de Señal , Animales , Animales Recién Nacidos , Línea Celular , GMP Cíclico/metabolismo , Pérdida del Embrión/metabolismo , Pérdida del Embrión/patología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Endotelio/metabolismo , Células Epiteliales/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Pulmón/ultraestructura , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Alveolos Pulmonares/patología , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , beta-Arrestinas/metabolismo
5.
Nat Commun ; 6: 6351, 2015 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-25690954

RESUMEN

While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.


Asunto(s)
Mama/metabolismo , Epigénesis Genética , Regulación de la Expresión Génica , Mama/citología , Ciclo Celular , Diferenciación Celular , Separación Celular , Cromatina/química , Inmunoprecipitación de Cromatina , Islas de CpG , Epigenómica , Células Epiteliales/citología , Exones , Femenino , Citometría de Flujo , Genoma Humano , Histonas/química , Humanos , Intrones , Cariotipificación , MicroARNs/metabolismo , Análisis de Secuencia de ARN , Transcripción Genética
6.
J Immunol ; 191(2): 892-901, 2013 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-23776175

RESUMEN

Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase ß. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.


Asunto(s)
Células Endoteliales/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Receptor Toll-Like 4/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Movimiento Celular , Activación Enzimática , Quinasa I-kappa B/metabolismo , Inmunidad Innata , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos/inmunología , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Interferencia de ARN , Transducción de Señal , Proteínas Supresoras de Tumor/genética , Ubiquitinación , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
7.
Dev Biol ; 377(2): 385-98, 2013 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-23458898

RESUMEN

Receptors expressed on the growth cone of outgrowing axons detect cues required for proper navigation. The pathway choices available to an axon are in part defined by the set of guidance receptors present on the growth cone. Regulated expression of receptors and genes controlling the localization and activity of receptors ensures that axons respond only to guidance cues relevant for reaching their targets. In genetic screens for axon guidance mutants, we isolated an allele of let-19/mdt-13, a component of the Mediator, a large ~30 subunit protein complex essential for gene transcription by RNA polymerase II. LET-19/MDT-13 is part of the CDK8 module of the Mediator. By testing other Mediator components, we found that all subunits of the CDK8 module as well as some other Mediator components are required for specific axon navigation decisions in a subset of neurons. Expression profiling demonstrated that let-19/mdt-13 regulates the expression of a large number of genes in interneurons. A mutation in the sax-3 gene, encoding a receptor for the repulsive guidance cue SLT-1, suppresses the commissure navigation defects found in cdk-8 mutants. This suggests that the CDK8 module specifically represses the SAX-3/ROBO pathway to ensure proper commissure navigation.


Asunto(s)
Axones/fisiología , Caenorhabditis elegans/embriología , Movimiento Celular/fisiología , Quinasa 8 Dependiente de Ciclina/metabolismo , Complejo Mediador/metabolismo , Sistema Nervioso/embriología , Animales , Cartilla de ADN/genética , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Conos de Crecimiento/metabolismo , Microscopía Confocal , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Interferencia de ARN , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Proteínas Roundabout
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