RESUMEN
BACKGROUND: Previous studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex. METHODS: We identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected. RESULTS: Forty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery. CONCLUSION: Despite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.
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Rasmussen's encephalitis (RE) is a rare chronic inflammatory brain disorder resulting in progressive neurodegeneration in one cerebral hemisphere. The inflammatory process is accompanied by progressive loss of function of the affected hemisphere, associated with drug-resistant partial epilepsy. The diagnosis is based on a range of clinical, electroencephalographic, radiological and biochemical arguments, without any specific formal marker, which makes the diagnosis of the disease complex, especially in its initial phase. Seizures are refractory to anti-seizures medication (ASM) and to classical immunomodulatory treatments. These treatments are also ineffective to stop the degenerative process. Only surgical treatment with hemispherotomy (surgical disconnection of a cerebral hemisphere) allows definitive cessation of seizures but this leads to definitive motor and cognitive deficits. The etiology of RE is not known, but there is strong evidence for an immunopathogenic mechanism involving T-cell mediated immunity. The emergence of biotherapies targeting against various cytokines offers potential therapeutic perspectives. This disease is currently a real challenge in terms of: (i) early diagnosis, before the constitution of marked hemispheric atrophy and the appearance of neurological and cognitive consequences; (ii) recognition of incomplete form; (iii) therapeutic management due to advances in the field of targeted treatment of inflammation; (iv) surgery and recovery possibilities.
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Encefalitis , Atrofia , Encéfalo/patología , Niño , Enfermedad Crónica , Diagnóstico Precoz , Electroencefalografía , Encefalitis/complicaciones , Encefalitis/diagnóstico , Encefalitis/terapia , Humanos , Imagen por Resonancia MagnéticaRESUMEN
In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl-)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3-11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2-18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.
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Trastorno del Espectro Autista/tratamiento farmacológico , Bumetanida/administración & dosificación , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/administración & dosificación , Adolescente , Anorexia/inducido químicamente , Astenia/inducido químicamente , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/psicología , Bumetanida/uso terapéutico , Niño , Preescolar , Deshidratación/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipopotasemia/inducido químicamente , Masculino , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Resultado del TratamientoRESUMEN
Early onset epileptic encephalopathies (EOEE) are heterogeneous group of severe epilepsies that still need to be better defined and characterized. On a genetic point of view, several dozen of genes have been associated with EOEE, and to date, it is difficult to find a common mechanism to explain EOEE. In this short review, we show that two mains genes are involved in EOEE: STXBP1 and KCNQ2. Focusing on KCNQ2 related EOEE, we show that a relatively similar phenotype can be related to various consequences of mutations on a single gene. This will probably challenge the treatment of EOEE patients.
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Convulsiones/genética , Convulsiones/terapia , Epilepsia/genética , Humanos , Recién Nacido , Medicina de Precisión , Convulsiones/diagnósticoRESUMEN
Autism spectrum disorder is associated with an altered early brain development. However, the specific cortical structure abnormalities underlying this disorder remain largely unknown. Nonetheless, atypical cortical folding provides lingering evidence of early disruptions in neurodevelopmental processes and identifying changes in the geometry of cortical sulci is of primary interest for characterizing these structural abnormalities in autism and their evolution over the first stages of brain development. Here, we applied state-of-the-art sulcus-based morphometry methods to a large highly-selective cohort of 73 young male children of age spanning from 18 to 108 months. Moreover, such large cohort was selected through extensive behavioral assessments and stringent inclusion criteria for the group of 59 children with autism. After manual labeling of 59 different sulci in each hemisphere, we computed multiple shape descriptors for each single sulcus element, hereby separating the folding measurement into distinct factors such as the length and depth of the sulcus. We demonstrated that the central, intraparietal and frontal medial sulci showed a significant and consistent pattern of abnormalities across our different geometrical indices. We also found that autistic and control children exhibited strikingly different relationships between age and structural changes in brain morphology. Lastly, the different measures of sulcus shapes were correlated with the CARS and ADOS scores that are specific to the autistic pathology and indices of symptom severity. Inherently, these structural abnormalities are confined to regions that are functionally relevant with respect to cognitive disorders in ASD. In contrast to those previously reported in adults, it is very unlikely that these abnormalities originate from general compensatory mechanisms unrelated to the primary pathology. Rather, they most probably reflect an early disruption on developmental trajectory that could be part of the primary pathology.
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Envejecimiento/patología , Trastorno del Espectro Autista/patología , Corteza Cerebral/patología , Niño , Preescolar , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Tamaño de los Órganos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
AIM: Mitochondrial disease is a heterogeneous disorder entity induced by defects in the mitochondrial respiratory chain complex. Neurological symptoms, including epilepsy, are common in children. The aim of this study was to research the clinical signs indicating mitochondrial disease. METHODS: We retrospectively studied epileptic children who underwent a muscle and/or hepatic biopsy between 1995 and 2010 searching for a mitochondrial disease. Patients were separated into 2 groups depending on the biopsy result: group 1 (presence of mitochondrial disease) and group 2 (absence of mitochondrial disease). Epileptic phenotypes were compared between these 2 groups. In group 1, we specified the clinical phenotype and characterized mitochondrial disease. RESULTS: Fifty-three children were included: 29 in group 1 and 24 in group 2. The average age at onset of epilepsy was 39.6 months in group 1 versus 11.8 months in group 2. In the 1st group, epilepsy was less refractory and associated with other clinical symptoms. CONCLUSIONS: In this study, epilepsy did not appear to be a unique sign of mitochondrial disease. It most often appeared during the 2nd year of life and is correlated with multiorgan involvement, notably ophthalmologic, such as oculomotor apraxia, optic atrophy, and retinitis pigmentosa, as well as auditory (deafness) and hepatic (hepatic failure, hepatomegaly). On the other hand, in children who did not have mitochondrial disease, epilepsy often began earlier (before 3 months of age), it was refractory, isolated without multiorgan involvement, and seems to be due to genetic anomalies in developmental genes, a finding that requires further research.
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Epilepsia/complicaciones , Enfermedades Mitocondriales/complicaciones , Biopsia , Niño , Preescolar , ADN Mitocondrial/genética , Femenino , Humanos , Lactante , Masculino , Enfermedades Mitocondriales/diagnóstico , Músculo Esquelético/patología , Mutación , Estudios RetrospectivosRESUMEN
UNLABELLED: The association of type 1 diabetes mellitus (DM) and epilepsy has been previously reported. However, the physiopathology of this association remains misunderstood. OBJECTIVE: To describe epilepsy combined with type 1 DM in children. METHODS: Retrospective monocentric study of all the epileptic and type 1 diabetic children consulting at the Timone University Hospital, Marseille, France. For each patient, the type of epilepsy and its electroclinical and radiographic characteristics were studied as well as the type of diabetes (biological characteristics, glycemic control), and the onset of these 2 diseases. RESULTS: Ten patients are reported. Five suffered from generalized epilepsy (4 idiopathic, 1 nonidiopathic) and 5 from focal epilepsy (4 non-idiopathic, 1 idiopathic). For most of these cases, presence of GAD (glutamic acid decarboxylase) autoantibodies were confirmed and epilepsy followed diabetes. CONCLUSIONS: The 2 most common types of epilepsy in this association are idiopathic generalized epilepsy and non-idiopathic temporal epilepsy. Several mechanisms could be involved (immune, glycemia, and genetic disorders).
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Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/complicaciones , Epilepsia Generalizada/complicaciones , Epilepsia del Lóbulo Temporal/complicaciones , Glutamato Descarboxilasa/sangre , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Estudios de Cohortes , Diabetes Mellitus Tipo 1/diagnóstico , Diagnóstico Diferencial , Epilepsia Generalizada/sangre , Epilepsia Generalizada/diagnóstico , Epilepsia del Lóbulo Temporal/sangre , Epilepsia del Lóbulo Temporal/diagnóstico , Femenino , Hospitales Universitarios , Humanos , Lactante , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y Especificidad , Distribución por SexoRESUMEN
Today, cardiovascular diseases (CVD) remain the principal cause of death in industrialized countries and are linked to obesity and metabolic syndrome. Metabolic syndrome is characterized by changes in arterial blood pressure, glucose metabolism, lipid and lipoprotein profiles in addition to inflammation. Adipose tissue produces many cytokines and secretory factors termed adipokines. Intra-abdominal (visceral) adipose tissue in particular, rather than peripheral, appears to be associated with global cardiometabolic risk. The present article summarizes information on five recently discovered adipokines: vaspin, visfatin, apelin, acylation stimulating protein (ASP) and retinol-binding protein 4 (RBP4) and their potential beneficial or deleterious roles in obesity and atherosclerosis. Vaspin may have antiatherogenic effects through its potential insulin-sensitizing properties. Similarly, visfatin has been suggested to enhance insulin sensitivity, but its potential role in plaque destabilization may counteract this. Apelin, via inhibition of food intake, and increases in physical activity and body temperature, may promote weight loss, resulting in a beneficial antiatherogenic effect. Further, favourable effects on vasodilatation and blood pressure add to this positive effect. Considering its increased levels in subjects with demonstrated atherosclerosis, RBP4 may constitute a biomarker. Lastly, ASP, often increased in obesity and metabolic disorders, may be contributing to efficient lipid storage, and decreasing or blocking ASP may provide a potential antiobesity target. Adipokines may further contribute to obesity-atherosclerosis relationships, the full understanding of which will require further research.
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Adipoquinas/metabolismo , Aterosclerosis/metabolismo , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Femenino , Humanos , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Obesidad/fisiopatologíaRESUMEN
Although LVT is currently extensively prescribed in childhood epilepsy, its effect on the panel of refractory epilepsy syndromes has not been entirely evaluated prospectively. In order to study the efficacy and safety of LVT as adjunctive therapy according to syndromes, we included 102 patients with refractory seizures (6 months to 15 years) in a prospective open-labeled trial. The responder rate was respectively 36% and 32% at 3 and 6 months with 6% and 7% patients becoming seizure free. Among the responders at 6 months (n=33), seizure frequency decreased by 66% and 79% at 3 and 6 months LVT compared to baseline. The highest benefit was for CSWS patients with 2/3 responders, 50% seizure free and no aggravation. LVT provided respectively 39% and 42% responders in focal and absence epilepsies. Infantile spasms and Dravet syndrome experienced the lowest efficacy. No patient with myoclonic-astatic epilepsy or Lennox-Gastaut syndrome was aggravated. LVT dose over 40 mg/kg/d was associated with a lower response rate. Tolerability was excellent. In spite of a small sample, we assume that CSWS is a good candidate for a randomized-controlled trial with LVT.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Piracetam/análogos & derivados , Adolescente , Anticonvulsivantes/farmacocinética , Niño , Preescolar , Femenino , Humanos , Lactante , Levetiracetam , Masculino , Piracetam/farmacocinética , Piracetam/uso terapéutico , Sueño/efectos de los fármacos , Sueño/fisiologíaRESUMEN
OBJECTIVE: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies. DESIGN AND SUBJECTS: The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations. RESULTS: All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients. CONCLUSION: A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.
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Encéfalo/enzimología , Encéfalo/patología , Complejo I de Transporte de Electrón/deficiencia , Imagen por Resonancia Magnética/métodos , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/patología , Adolescente , Adulto , Niño , Preescolar , Complejo I de Transporte de Electrón/genética , Femenino , Humanos , Lactante , Leucoencefalopatías/complicaciones , Leucoencefalopatías/patología , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/genética , Mutación/genética , Complejo Piruvato Deshidrogenasa/genética , Radiografía , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/patología , Adulto JovenAsunto(s)
Logro , Trastornos del Conocimiento/rehabilitación , Epilepsia/rehabilitación , Discapacidades para el Aprendizaje/rehabilitación , Rehabilitación Vocacional , Adaptación Psicológica , Adolescente , Niño , Preescolar , Trastornos del Conocimiento/psicología , Educación Especial , Epilepsia/psicología , Estudios de Seguimiento , Humanos , Discapacidades para el Aprendizaje/psicología , Grupo de Atención al Paciente , Ajuste SocialRESUMEN
PURPOSE: Morphologic abnormalities of the hippocampal formations (MAHF) are more frequently observed in magnetic resonance imaging (MRI). We wished to specify the types of disorders associated with these malformations based on a retrospective case series by studying the language of the children presenting these abnormalities. PATIENTS AND METHODS: From the data of all the MRIs taken in the neuroradiology ward of our center over 16 months in patients under 18 years of age, we retrospectively selected the children with an MAHF, isolated or associated with other malformations. The MAHFs were defined and described according to criteria of shape or orientation defects of the hippocampal formations. We studied the files of the patients with isolated MAHF again. Those whose clinical presentation was compatible with language assessment were tested in a prospective approach. RESULTS: Out of 2208 MRIs from 1 January 2007 to 30 April 2008, 96 (4.3%) showed an MAHF, including 61 (64%) boys and 35 (36%) girls, aged from 2 months to 17 years. Eighty-two (85%) had associated abnormalities, mainly including cerebral atrophy, corpus callosum agenesis or defect, and abnormal ventricular frontal horns. Fourteen (15%) had an isolated MAHF: 2 on the left hemisphere, 2 on the right hemisphere, and 10 on both. Of these 14, 9 were compatible with language assessment. From the test results, we divided these children into 2 groups, depending on the type and severity of the impairment. Four had very serious language disorders as part of mental retardation or autistic disorders; 4 others had language disorders predominantly in expression and phonology, with weak to pathological visual memory. This study showed no potential relation between the lateralization of MAHF and language disorders, nor between the existence of epilepsy and the severity of the language disorders. Of these 14 children, 9 had behavior and autism spectrum disorders and 7 were epileptic. CONCLUSION: Even though language disorders are often part of a larger deficiency presentation, the results we obtained suggest that isolated MAHFs are not only causes of amnestic disorders, but they could also directly underlie language disorders, particularly in expression.
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Hipocampo/anomalías , Hipocampo/patología , Trastornos del Lenguaje/diagnóstico , Imagen por Resonancia Magnética , Adolescente , Trastorno Autístico/diagnóstico , Niño , Preescolar , Femenino , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Trastornos del Lenguaje/etiología , Masculino , Estudios RetrospectivosRESUMEN
Although status epilepticus (SE) affects the course of Dravet syndrome (DS), it rarely alters dramatically psychomotor outcome. We report an unusual pattern in 3 patients who following refractory SE lasting respectively 2, 7 and 12h experienced persistent and severe cognitive and motor deterioration. We compared these patients to published data and to personal experience in Necker hospital, to find links between severe outcome and clinical features such as treatment or duration of refractory SE. The key point was that anoxoischemic-like lesions appeared on MRI although cardiovascular function had remained stable. Therefore, neither hemodynamic failure, nor abnormalities of cardiac rhythm could explain the lesions and neurological worsening. For theoretical reasons the responsibility of therapy common for the 3 patients, e.g., barbiturates was suspected.
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Encéfalo/patología , Epilepsia/patología , Estado Epiléptico/patología , Anticonvulsivantes/efectos adversos , Barbitúricos/efectos adversos , Encéfalo/irrigación sanguínea , Preescolar , Discapacidades del Desarrollo/etiología , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Humanos , Lactante , Imagen por Resonancia Magnética , Mutación , Canal de Sodio Activado por Voltaje NAV1.1 , Proteínas del Tejido Nervioso/genética , Canales de Sodio/genética , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/genética , Tomografía Computarizada por Rayos XRESUMEN
Seizures are the most common pediatric neurologic disorder. This article describes the guidelines of the French Pediatric Neurology Society, highlighting the importance of a thorough history and examination. Paroxysmal nonepileptic events should be excluded. The role of biological and neuroradiological investigations is discussed. An electroencephalographic recording and advice from a pediatric neurologist are suggested.
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Convulsiones/diagnóstico , Niño , Preescolar , Humanos , Lactante , Convulsiones/etiologíaRESUMEN
GLUT-1 protein is the principal glucose transporter across the blood-brain barrier. GLUT-1 deficiency results in a syndrome of infantile seizures refractory to anticonvulsive drugs, developmental delay, acquired microcephaly and neurologic manifestations including spasticity, hypotonia, and ataxia. A low cerebrospinal fluid glucose concentration in the absence of hypoglycaemia is pathognomonic of glucose transporter deficiency syndrome. Ketogenic diet is an effective treatment of epileptic manifestations but it has less effect on the cognitive symptoms. We report on a child who presented with paroxistical events often occurring prior to meals, developmental delay, microcephaly and spasticity. CSF and serum glucose levels measured simultaneously showed a CSF/serum glucose ratio of 0.39. Molecular analysis identified a heterozygous novel mutation.
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Errores Innatos del Metabolismo de los Carbohidratos , Transportador de Glucosa de Tipo 1/deficiencia , Ataxia/complicaciones , Glucemia/análisis , Barrera Hematoencefálica , Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Errores Innatos del Metabolismo de los Carbohidratos/dietoterapia , Errores Innatos del Metabolismo de los Carbohidratos/genética , Epilepsia/complicaciones , Epilepsia/etiología , Glucosa/líquido cefalorraquídeo , Heterocigoto , Humanos , Lactante , Masculino , Microcefalia/complicaciones , Hipotonía Muscular/complicaciones , Mutación , SíndromeRESUMEN
Epileptic seizures can be difficult to recognize in infancy and childhood because the semeiology can be misleading. Already, in the acute phase, precise assessment of the seizure is required, with active questioning about circumstances of occurrence, clinical manifestations and postictal symptoms. Laboratory tests and toxicologic screening should only be performed according to the circumstances and clinical examination in order to distinguish between symptomatic seizure and epilepsy at the beginning. Epilepsy consists in repetition of several unprovoked epileptic seizure. Assessment of the age of onset, type of seizures, interictal EEG and the neuropsychological profile are instrumental for both the diagnosis of epileptic syndrome and the choice of the right treatment. Epileptic seizures cause distress to parents and the fear they experience of death must always be taken into account.
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Epilepsia/diagnóstico , Convulsiones/diagnóstico , Adolescente , Factores de Edad , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Niño , Diagnóstico Diferencial , Electroencefalografía , Epilepsias Parciales/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia Tipo Ausencia/diagnóstico , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Epilepsia Mioclónica Juvenil/diagnóstico , Convulsiones/tratamiento farmacológico , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/tratamiento farmacológico , Vigabatrin/administración & dosificación , Vigabatrin/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Ivabradine, a specific and use-dependent I(f) inhibitor, exerts anti-ischaemic activity purely by reducing heart rate. The aim of this work was to characterize its effect on the predominant HCN channel isoform expressed in human sino-atrial nodes (hSAN), to determine its kinetics in HCN channels from multicellular preparations and rate-dependency of its action. EXPERIMENTAL APPROACH: RT-PCR analysis of the four HCN channel isoforms was carried out on RNAs from hSAN. Patch-clamp and intracellular recordings were obtained from CHO cells stably expressing hHCN4 and isolated SAN, respectively. Beating rate of rat isolated atria was followed using a transducer. KEY RESULTS: hHCN4 mRNAs were predominant in hSAN. Ivabradine induced a time-dependent inhibition of hHCN4 with an IC(50) of 0.5 microM. In rabbit SAN, ivabradine progressively reduced the frequency of action potentials: by 10% after 3 h at 0.1 microM, by 14% after 2 h at 0.3 microM and by 17% after 1.5 h at 1 microM. After 3h, ivabradine reduced the beating rate of rat right atria with an IC(30) of 0.2 microM. The onset of action of ivabradine was use-dependent rather than time-dependent with slower effects than caesium, an extracellular I (f) blocker. Ivabradine 3 microM decreased the frequency of action potentials in SAN from guinea-pig, rabbit and pig by 33%, 21% and 15% at 40 min, respectively. CONCLUSIONS AND IMPLICATIONS: The use-dependent inhibition of hHCN4 current by ivabradine probably contributes to its slow developing effect in isolated SAN and right atria and to its increased effectiveness in species with rapid SAN activity.
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Benzazepinas/farmacología , Relojes Biológicos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Canales Iónicos/antagonistas & inhibidores , Proteínas Musculares/antagonistas & inhibidores , Potenciales de Acción/efectos de los fármacos , Animales , Células CHO , Cricetinae , Cricetulus , Canales Catiónicos Regulados por Nucleótidos Cíclicos , Femenino , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Canales Iónicos/genética , Ivabradina , Masculino , Proteínas Musculares/genética , Canales de Potasio , ARN Mensajero/genética , Conejos , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , PorcinosRESUMEN
Benzodiazepines (Bzd) are known to interact with GABAergic inhibitory neurotransmission. Previous research on their effect on human auditory efferent pathways--through evoked otoacoustic emissions suppression by contralateral acoustic stimulation (CAS)--indicated a decrease in medial olivocochlear (MOC) efferent system inhibitory activity, after oral intake of oxazepam--representative of the Bzd drug class. To date, this pharmacological effect was only assessed in the right ear. Since a leftward asymmetry of Bzd receptors localization in human auditory cortex has been described recently, we explored in this study the hypothesis of an asymmetrical action of Bzd on MOC efferent functioning. The results revealed a significant difference of Bzd effect probing the right ear versus the left ear, with CAS-induced suppression being less effective in the right than left ear after oxazepam intake. This finding raises the question of possible neurochemical left-right asymmetry in the descending auditory pathways. The potential localization of this asymmetry is discussed.