Publications by authors named "Kiyoshi Egawa"

31 Publications

Selective Eating in Autism Spectrum Disorder Leading to Hair Color Change.

Pediatr Neurol 2021 Jul 2;120:1-2. Epub 2021 Apr 2.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2021.03.001DOI Listing
July 2021

Selective Eating in Autism Spectrum Disorder Leading to Kwashiorkor and Brain Edema.

Pediatr Neurol 2021 03 26;116:55-56. Epub 2020 Dec 26.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2020.12.007DOI Listing
March 2021

Variance in the pathophysiological impact of the hemizygosity of gamma-aminobutyric acid type A receptor subunit genes between Prader-Willi syndrome and Angelman syndrome.

Brain Dev 2021 Apr 5;43(4):521-527. Epub 2021 Jan 5.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Electronic address:

Introduction: Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders caused by loss of function of maternally expressed UBE3A and paternally expressed contiguous genes on chromosome 15q11-13, respectively. A majority of these syndromes suffer from a large deletion of the relevant chromosome (AS Del or PWS Del), which includes biallelically expressed gamma-aminobutyric acid type A receptor subunit (GABAaR) genes, while remaining individuals present without the deletion (AS non-Del or PWS non-Del). We previously reported that AS Del, but not AS non-Del individuals, show aberrantly desynchronized somatosensory-evoked magnetic fields (SEFs) and speculated that it might reflect GABAergic dysfunction due to the hemizygosity of GABAaR genes. To verify its pathophysiological impact on PWS and AS, we analyzed the SEFs of PWS individuals.

Method: SEFs were recorded from eight PWS Del and two PWS non-Del individuals. The latency and strength of the first peak (N1m) were compared with those of AS Del/non-Del individuals and controls, most of which were obtained earlier.

Results: In contrast to AS, both PWS Del and PWS non-Del showed normal SEF waveforms. Desynchronized response with delayed N1m peak latency was exclusively indicated in AS Del. N1m strength was statistically higher in AS Del and AS non-Del, but not in PWS Del and PWS non-Del.

Conclusions: Our results indicate that the pathophysiological impact of the hemizygosity of GABAaR genes is lower in PWS than AS. UBE3A deficiency and the hemizygosity of GABAaR genes could synergistically deteriorate neuronal function, resulting in aberrant SEFs in AS Del.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.12.014DOI Listing
April 2021

Flurothyl-induced seizure paradigm revealed higher seizure susceptibility in middle-aged Angelman syndrome mouse model.

Brain Dev 2021 Apr 4;43(4):515-520. Epub 2021 Jan 4.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan. Electronic address:

Introduction: Epilepsy is one of the main clinical problems in Angelman syndrome (AS). Seizures typically start in early childhood then decrease or are often alleviated by young adulthood. Several studies using AS model mice showed comparable seizure susceptibility during young adulthood. In contrast, the course of epilepsy post young adulthood differs from persistently relieved to rerising among reports. To elucidate this, we evaluated the seizure susceptibility of AS model mice of two different ages.

Methods: Mice lacking maternal Ube3a gene (Ube3a) of C57BL/6 background or their littermate wild type (WT) were divided into two groups by age, 2 to 3 months (2-3 M) and 6 to 12 months (6-12 M), corresponding to adolescent to young adult aged and middle aged humans, respectively. Seizure susceptibility was evaluated by flurothyl inhalation or intraperitoneal injection of pentylenetetrazole (PTZ IP)-induced acute seizure protocol.

Results: In the flurothyl-induced seizure paradigm, the latency to seizure occurrence had a significant interaction with genotype and age. Post-hoc analysis revealed that the latency was significantly shorter at 6-12 M than at 2-3 M in Ube3a mice, and in Ube3a mice than in WT mice at 6-12 M. No significant interaction or difference was observed by PTZ IP.

Conclusion: The flurothyl-induced seizure paradigm revealed that seizure susceptibility of Ube3a mice increased with age, similar to clinical studies reporting the reappearance of epilepsy in older age. The flurothyl-induced seizure paradigm applied to middle-aged Ube3a mice could be a suitable protocol for screening drugs against seizures in AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.12.011DOI Listing
April 2021

Reinterpretation of magnetic resonance imaging findings with magnetoencephalography can improve the accuracy of detecting epileptogenic cortical lesions.

Epilepsy Behav 2021 01 13;114(Pt A):107516. Epub 2020 Dec 13.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. Electronic address:

Objective: This study examined whether the application of magnetoencephalography (MEG) to interpret magnetic resonance imaging (MRI) findings can aid the diagnosis of intractable epilepsy caused by organic brain lesions.

Methods: This study included 51 patients with epilepsy who had MEG clusters but whose initial MRI findings were interpreted as being negative for organic lesions. Three board-certified radiologists reinterpreted the MRI findings, utilizing the MEG findings as a guide. The degree to which the reinterpretation of the imaging results identified an organic lesion was rated on a 5-point scale.

Results: Reinterpretation of the MRI data with MEG guidance helped detect an abnormality by at least one radiologist in 18 of the 51 patients (35.2%) with symptomatic localization-related epilepsy. A surgery was performed in 7 of the 51 patients, and histopathological analysis results identified focal cortical dysplasia in 5 patients (Ia: 1, IIa: 2, unknown: 2), hippocampal sclerosis in 1 patient, and dysplastic neurons/gliosis in 1 patient.

Conclusions: The results of this study highlight the potential diagnostic applications of MEG to detect organic epileptogenic lesions, particularly when radiological visualization is difficult with MRI alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107516DOI Listing
January 2021

Reply to the letter: "Perampanel may be beneficial in leigh syndrome by its anti-oxidative but not anti-epileptic effect".

Brain Dev 2021 02 13;43(2):361-362. Epub 2020 Dec 13.

Department of Pediatrics, Teine Keijinkai Hospital, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.10.008DOI Listing
February 2021

Short-latency somatosensory-evoked potentials demonstrate cortical dysfunction in patients with Angelman syndrome.

eNeurologicalSci 2021 Mar 1;22:100298. Epub 2020 Dec 1.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo 060-8638, Japan.

Background: Angelman syndrome (AS) is neurodevelopmental disorder, causal gene of which is maternally expressed . A majority of patients results from the large deletion of relevant chromosome which includes GABA receptor subunit genes (GABARs) as well as (AS Del) We previously reported aberrantly desynchronized primary somatosensory response in AS Del by using magnetoencephalography. The purpose of this study is to estimate cortical and subcortical involvement in the deficit of primary somatosensory processing in AS.

Methods: We analyzed short-latency somatosensory-evoked potentials (SSEPs) in 8 patients with AS Del. SSEPs were recorded on a 4-channel system comprising of two cortical electrodes which were placed on the frontal and centro-parietal areas. The peak and onset latency of each component were measured to compare latency and interval times.

Results: The first-cortical peak latency (N20, P20), and N13-N20 peak interval times were significantly prolonged in AS Del compared to healthy controls. In contrast, there was no difference in latencies between subcortical components up to N20 onset or for N11-N20 onset interval times.

Conclusion: Highly desynchronized first-cortical SSEP components and normal latencies of subcortical components indicated cortical dysfunction rather than impairment of afferent pathways in AS Del patients, which might be attributed to GABAergic dysfunction due to loss of function and heterozygosity of GABARs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ensci.2020.100298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721653PMC
March 2021

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency.

Brain Dev 2021 Feb 11;43(2):214-219. Epub 2020 Aug 11.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, Research and Development Division, Japan.

Background: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks.

Patients And Methods: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions.

Results: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment.

Conclusion: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.07.019DOI Listing
February 2021

Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report.

Brain Dev 2021 Jan 29;43(1):157-159. Epub 2020 Jul 29.

Department of Pediatrics, Nikko Memorial Hospital, Japan.

Background: Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug.

Case Presentation: A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved.

Conclusion And Discussion: Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.07.008DOI Listing
January 2021

Perampanel for nonepileptic myoclonus in Angelman syndrome.

Brain Dev 2020 May 10;42(5):389-392. Epub 2020 Mar 10.

Department of Pediatrics, Hokkaido University Hospital, Japan. Electronic address:

Background: Angelman syndrome (AS) is a neurodegenerative disorder caused by functional loss of the maternal ubiquitin-protein ligase 3A gene. Nonepileptic myoclonus, also described as tremulous movement, often occurs during puberty and increases in adulthood. The involuntary movement in AS has not been defined patho-physiologically and the drugs used such as levetiracetam and piracetam are not always effective. Recently, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, perampanel (PER), was used to alleviate myoclonus in progressive myoclonus epilepsy. Herein, we tested the efficacy of PER for nonepileptic myoclonus.

Methods And Results: Four patients with AS, aged from 20 to 40 years at the beginning of treatment, were enrolled in our study. All patients reported disruption to their daily lives from the myoclonus movement. They experienced mild to moderate improvement with the starting dose of 2 mg. The dose was increased to 4 mg in one patient to achieve sufficient efficacy, while two had their dose reduced to 1 mg due to dizziness or possible exacerbation of myoclonus. The last patient continued to take the starting dose. Follow-up over 16-20 months revealed a significant reduction in the severity of nonepileptic myoclonus in all patients.

Conclusion: Our study suggests that PER could be one of the promising drugs for nonepileptic myoclonus in AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2020.02.007DOI Listing
May 2020

Diverse Actions of Astrocytes in GABAergic Signaling.

Int J Mol Sci 2019 Jun 18;20(12). Epub 2019 Jun 18.

Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the "tripartite" synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20122964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628243PMC
June 2019

Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene.

Brain Dev 2018 Mar;40(3):226-228

Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan.

Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30 s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis. Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient's younger years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2017.11.007DOI Listing
March 2018

Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA).

Epilepsy Behav Case Rep 2017 26;8:44-46. Epub 2017 May 26.

Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

We administered perampanel (PER) to a bedridden 13-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA). The DRPLA diagnosis was based on the presence of a CAG trinucleotide repeat in the gene. The patient experienced continuous myoclonic seizures and weekly generalized tonic-clonic seizures (GTCs). PER stopped the patient's myoclonic seizures and reduced the GTCs to fragmented clonic seizures. The patient recovered his intellectual abilities and began to walk again with assistance. We suggest that PER be considered as one of the key drugs used to treat patients with DRPLA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebcr.2017.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565628PMC
May 2017

Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential.

Trends Neurosci 2017 05 18;40(5):276-294. Epub 2017 Apr 18.

Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl concentration ([Cl]) regulation impacts on both cell volume homeostasis and Cl-permeable GABA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl] - cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl transporters - could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Cl cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. We establish here a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl] and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl] that are relevant for two common clinical sequela of brain injury: edema and seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tins.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473173PMC
May 2017

The presence of short and sharp MEG spikes implies focal cortical dysplasia.

Epilepsy Res 2015 Aug 12;114:141-6. Epub 2015 May 12.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15 West 7, Kita-ku, Sapporo, Japan. Electronic address:

Purpose: This study focused on the characteristic needle-like epileptic spikes of short duration and steep shape seen on magnetoencephalography (MEG) in patients diagnosed with focal cortical dysplasia (FCD) morphologically. We aimed to validate the analysis of MEG spike morphology as a noninvasive method of identifying the presence and location of FCD.

Methods: MEG was collected by 204-channel helmet-shaped gradiometers. We analyzed MEG spike sources for 282 patients with symptomatic localization-related epilepsy. MEG showed clustered equivalent current dipoles when superimposed on their three-dimensional-magnetic resonance images (MRI) in 85 patients. Fifty-seven patients were excluded from our study, because they had destructive brain lesions or an insufficient number of spikes for statistical analysis. Twenty-eight patients (18 males, 10 females; aged 1-34 years) were finally matched to our inclusion criteria, and were categorized into three groups: FCD (7 patients), non-FCD (10 patients), and non-lesion (11 patients), based on the MRI findings. We measured the duration, amplitude, and tilt manually for at least 15 spikes per patient, and compared the three groups using a one-way analysis of variance, followed by the Tukey test when statistically significant (p < 0.05). In 17 patients with visible MRI lesions, we investigated the correlation between the depth of the lesion and the tilt using the Pearson product moment correlation.

Results: The average spike duration was significantly shorter in the FCD and non-lesion groups than in the non-FCD group (p < 0.05). The average amplitude was not significantly different between the three groups. The average spike tilt was significantly steeper in the FCD group than in the non-FCD group (p = 0.0058). There was no significant difference between FCD and non-lesion patients in both duration and tilt. Our additional study revealed a significant negative correlation between the depth of the lesion and the average tilt (p = 0.0009).

Significance: MEG epileptiform discharges of short duration and steep tilt characterize FCD, especially when located at the superficial neocortical gyrus. We speculate that this particular spike morphology results from the intrinsic epileptogenicity of FCD. Morphological analysis of MEG spikes can evaluate the etiology of epileptogenic lesions and detect a strong, localized epileptogenic focus such as that typically observed in FCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2015.04.020DOI Listing
August 2015

Pathophysiological power of improper tonic GABA(A) conductances in mature and immature models.

Front Neural Circuits 2013 24;7:170. Epub 2013 Oct 24.

Department of Neurology, Massachusetts General Hospital Charlestown, MA, USA ; Department of Pediatrics, Hokkaido University Graduate School of Medicine Sapporo, Japan.

High-affinity extrasynaptic gamma-aminobutyric acid A (GABA(A)) receptors are tonically activated by low and consistent levels of ambient GABA, mediating chronic inhibition against neuronal excitability (tonic inhibition) and the modulation of neural development. Synaptic (phasic) inhibition is spatially and temporally precise compared with tonic inhibition, which provides blunt yet strong integral inhibitory force by shunting electrical signaling. Although effects of acute modification of tonic inhibition are known, its pathophysiological significance remains unclear because homeostatic regulation of neuronal excitability can compensate for long-term deficit of extrasynaptic GABA(A) receptor activation. Nevertheless, tonic inhibition is of great interest for its pathophysiological involvement in central nervous system (CNS) diseases and thus as a therapeutic target. Together with the development of experimental models for various pathological states, recent evidence demonstrates such pathological involvements of tonic inhibition in neuronal dysfunction. This review focuses on the recent progress of tonic activation of GABA(A) conductance on the development and pathology of the CNS. Findings indicate that neuronal function in various brain regions are exacerbated with a gain or loss of function of tonic inhibition by GABA spillover. Disturbance of tonic GABA(A) conductance mediated by non-synaptic ambient GABA may result in brain mal-development. Therefore, various pathological states (epilepsy, motor dysfunctions, psychiatric disorders, and neurodevelopmental disorders) may be partly attributable to abnormal tonic GABA(A) conductances. Thus, the tone of tonic conductance and level of ambient GABA may be precisely tuned to maintain the regular function and development of the CNS. Therefore, receptor expression and factors for regulating the ambient GABA concentration are highlighted to gain a deeper understanding of pathology and therapeutic strategy for CNS diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncir.2013.00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807051PMC
April 2014

Cl⁻ homeodynamics in gap junction-coupled astrocytic networks on activation of GABAergic synapses.

J Physiol 2013 Aug 3;591(16):3901-17. Epub 2013 Jun 3.

Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

The electrophysiological properties and functional role of GABAergic signal transmission from neurons to the gap junction-coupled astrocytic network are still unclear. GABA-induced astrocytic Cl⁻ flux has been hypothesized to affect the driving force for GABAergic transmission by modulating [Cl⁻]o. Thus, revealing the properties of GABA-mediated astrocytic responses will deepen our understanding of GABAergic signal transmission. Here, we analysed the Cl⁻ dynamics of neurons and astrocytes in CA1 hippocampal GABAergic tripartite synapses, using Cl⁻ imaging during GABA application, and whole cell recordings from interneuron-astrocyte pairs in the stratum lacunosum-moleculare. Astrocytic [Cl⁻]i was adjusted to physiological conditions (40 mm). Although GABA application evoked bidirectional Cl⁻ flux via GABAA receptors and mouse GABA transporter 4 (mGAT4) in CA1 astrocytes, a train of interneuron firing induced only GABAA receptor-mediated inward currents in an adjacent astrocyte. A GAT1 inhibitor increased the interneuron firing-induced currents and induced bicuculline-insensitive, mGAT4 inhibitor-sensitive currents, suggesting that synaptic spillover of GABA predominantly induced the astrocytic Cl⁻ efflux because GABAA receptors are localized near the synaptic clefts. This GABA-induced Cl⁻ efflux was accompanied by Cl⁻ siphoning via the gap junctions of the astrocytic network because gap junction inhibitors significantly reduced the interneuron firing-induced currents. Thus, Cl⁻ efflux from astrocytes is homeostatically maintained within astrocytic networks. A gap junction inhibitor enhanced the activity-dependent depolarizing shifts of reversal potential of neuronal IPSCs evoked by repetitive stimulation to GABAergic synapses. These results suggest that Cl⁻ conductance within the astrocytic network may contribute to maintaining GABAergic synaptic transmission by regulating [Cl⁻]o.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/jphysiol.2013.257162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764636PMC
August 2013

Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.

Sci Transl Med 2012 Dec;4(163):163ra157

Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Motor dysfunction is a characteristic feature of Angelman syndrome, but neither the mechanisms of action nor effective therapeutic strategies have yet been elucidated. We report that tonic inhibition is specifically decreased in cerebellar granule cells of Ube3a-deficient mice, a model of Angelman syndrome. As a mechanism underlying this decrease in tonic inhibition, we show that Ube3a controls degradation of γ-aminobutyric acid (GABA) transporter 1 (GAT1) and that deficiency of Ube3a induces a surplus of GAT1 that results in a decrease in GABA concentrations in the extrasynaptic space. Administering low doses of 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP), a selective extrasynaptic GABA(A) receptor agonist, improves the abnormal firing properties of a population of Purkinje cells in cerebellar brain slices and reduces cerebellar ataxia in Ube3a-deficient mice in vivo. These results suggest that pharmacologically increasing tonic inhibition may be a useful strategy for alleviating motor dysfunction in Angelman syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.3004655DOI Listing
December 2012

Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.

Am J Hum Genet 2010 Jun 20;86(6):881-91. Epub 2010 May 20.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2010.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032058PMC
June 2010

Electroclinical features of epilepsy in patients with juvenile type dentatorubral-pallidoluysian atrophy.

Epilepsia 2008 Dec 26;49(12):2041-9. Epub 2008 Jun 26.

National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan.

Purpose: To clarify the electroclinical characteristics of epileptic seizures in patients with juvenile type dentatorubral-pallidoluysian atrophy (DRPLA).

Methods: Seventeen patients with juvenile type DRPLA confirmed by genetic analysis were studied retrospectively. The clinical records of all 17 patients and the ictal video electroencephalography (EEG) recordings from 12 of the 17 patients were reviewed.

Results: Electroclinical studies in 12 patients identified 11 habitual seizures in 6 patients as partial seizures on ictal video EEG recordings. Clinical manifestations composed mainly of versions of the head and loss of consciousness. These partial seizures were persistently recorded throughout the clinical course. Brief generalized seizures (atypical absence and myoclonic seizure) were observed in 6 of 12 patients at the early stage. In contrast, generalized tonic-clonic seizures (GTCS) were recorded in four advanced stage patients who were almost bedridden. Semiological studies in 17 patients showed that the prevalence of partial seizures was significantly higher in patients with younger epilepsy onset (below 10 years of age; chi(2) test, p < 0.05) and that the age of epilepsy onset was significantly lower in patients with partial seizures than in those without partial seizures (Mann-Whitney U test, p = 0.02). However, the number of CAG repeats and age at clinical onset were not significantly different between two groups.

Discussion: Partial seizure is one of the common epileptic features in juvenile type DRPLA, especially in patients with younger epilepsy onset. Seizure types may be affected in an age-dependent manner and change evolutionally during progression of the clinical stage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2008.01701.xDOI Listing
December 2008

[(11)C]flumazenil positron emission tomography analyses of brain gamma-aminobutyric acid type A receptors in Angelman syndrome.

J Pediatr 2008 Apr 5;152(4):546-9, 549.e1-3. Epub 2007 Nov 5.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Objective: To evaluate the role of the gamma-aminobutyric acid type A (GABA(A)) receptor in Angelman syndrome (AS).

Study Design: We performed [(11)C]flumazenil positron emission tomography (PET) and examined GABA(A) receptor expression in 7 patients with AS of various genotypes (5 with the deletion, 1 with an imprinting defect [ID], and 1 with a UBE3A mutation) and 4 normal control healthy volunteers.

Results: Relative to the control subjects, the [(11)C]flumazenil binding potentials (BPs) were significantly higher in the cerebral cortex and cerebellum in the 5 patients with the deletion and in the 1 patient with a UBE3A mutation, and were less frequently or barely increased in adult patients with the deletion and in the patient with IDs.

Conclusions: Total GABA(A) receptor expression was increased in patients with AS with various genotypes. We suggest that a developmental dysregulation of the GABA(A) receptor subunits occurs in patients with AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2007.08.038DOI Listing
April 2008

Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome.

Neuroimage 2008 Jan 15;39(2):593-9. Epub 2007 Sep 15.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan.

A role for gamma-aminobutyric acid (GABA)ergic inhibition in cortical sensory processing is one of the principle concerns of brain research. Angelman syndrome (AS) is thought to be one of the few neurodevelopmental disorders with GABAergic-related genetic involvement. AS results from a functional deficit of the imprinted UBE3A gene, located at 15q11-q13, resulting mainly from a 4-Mb deletion that includes GABA(A) receptor subunit genes. These genes are believed to affect the GABAergic system and modulate the clinical severity of AS. To understand the underlying cortical dysfunction, we have investigated the primary somatosensory-evoked responses in AS patients. Subjects included eleven AS patients with a 15q11-q13 deletion (AS Del), two AS patients without a 15q11-q13 deletion, but with a UBE3A mutation (AS non-Del), six epilepsy patients (non-AS) and eleven normal control subjects. Somatosensory-evoked fields (SEFs) in response to median nerve stimulation were measured by magnetoencephalography. The N1m peak latency in AS Del patients was significantly longer (34.6+/-4.8 ms) than in non-AS patients (19.5+/-1.2 ms, P<0.001) or normal control subjects (18.4+/-1.8 ms, P<0.001). The next component, P1m, was prolonged and ambiguous and was only detected in patients taking clonazepam. In contrast, SEF waveforms of AS non-Del patients were similar to those of control individuals, rather than to AS Del patients. Thus, GABAergic dysfunction in AS Del patients is likely due to hemizygosity of GABA(A) receptor subunit genes, suggesting that GABAergic inhibition plays an important role in synchronous activity of human sensory systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2007.09.006DOI Listing
January 2008

Induction of matrix metalloproteinase gene expression in an endothelial cell line by direct interaction with malignant cells.

Cancer Sci 2007 Jan;98(1):58-67

Department of Microbiology, Showa University School of Pharmaceutical Sciences, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.

Mouse endothelial TKD2 cells in monolayers were cocultured with various human cell lines for 24 h, and the expression of several secreted matrix metalloproteinases (MMP) and cell adhesion molecules was examined by real-time reverse transcription-polymerase chain reaction using mouse-specific primers. Coculture with normal fibroblasts did not elicit the expression of these molecules, but coculture with cancer cells induced the expression of MMP-3, MMP-9 and MMP-10 mRNA in endothelial cells, and in normal mouse embryonic fibroblasts. The induction of MMP mRNA was dependent on direct cell adhesion, as separate culture of A549 cells in Boyden chambers did not induce MMP mRNA, and neutralizing antibody against VLA-4 abolished the induction. An inhibitor of phosphatidylinositol-3-phosphate kinase strongly suppressed the induction of MMP-3, MMP-9 and MMP-10 mRNA, and expression of the dominant-negative mutant of phosphatidylinositol-3-phosphate kinase also decreased the induction. It was suggested that intracellular reactive oxygen species (ROS) levels were increased in TKD2 cells following adhesion to cancer cells. ROS scavengers decreased the levels of MMP induction, and roterone, an inhibitor of mitochondrial complex I, strongly suppressed the induction of MMP-3, MMP-9 and MMP-10. The depletion of mitochondria in TKD2 cells decreased the induction of MMP-9, but the induction of MMP-3 and MMP-10 was not affected. These results indicate that the adhesion of cancer cells to endothelial cells activates several distinct signaling pathways to induce MMP gene expression, and the pathways for MMP-3, MMP-9 and MMP-10 are partly different. For the induction of MMP-9, mitochondria participate in induction, possibly through the production of ROS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1349-7006.2006.00344.xDOI Listing
January 2007

Anthracyclines, small-molecule inhibitors of hypoxia-inducible factor-1 alpha activation.

Biol Pharm Bull 2006 Oct;29(10):1999-2003

Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Miyamoto, Shizuoka, Japan.

Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. To identify small molecule inhibitors of the HIF-1 transcriptional activation, we have established a high through-put assay system using a stable transformant of mammalian cells that express the luciferase reporter gene construct containing a HIF-1 binding site. Using this system, we screened 5000 cultured broths of microorganisms, and we found that cinerubin (1-hydroxy aclacinomycin B) showed a significant inhibition of the reporter activity induced by hypoxic conditions. In addition, we demonstrated that aclarubicin also inhibited the HIF-1 transcriptional activity under hypoxic conditions, but neither doxorubicin nor daunorubicin inhibited it. Consistent with these results, cinerubin and aclarubicin inhibited the hypoxic induction of the vascular endothelial growth factor (VEGF) protein in HepG2 cells, but neither doxorubicin nor daunorubicin affected it. Thus, our results suggested that some anthracyclines are also acting as angiogenesis inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.29.1999DOI Listing
October 2006

Inhibition of angiogenesis and HIF-1alpha activity by antimycin A1.

Biol Pharm Bull 2006 Jul;29(7):1344-8

Department of Microbiology, Showa University of Pharmaceutical Sciences, Tokyo, Japan.

We identified antimycin A1 as an inhibitor of the hypoxia-response element (HRE) from screening using a reporter under the control of HRE under hypoxic conditions. Antimycin A1 was effective at 20 pg/ml in inhibiting the reporter activity. The expression of vascular endothelial growth factor (VEGF) mRNA during hypoxia was also inhibited by antimycin A1. Angiogenesis induced by implantation of mouse sarcoma-180 cells was significantly inhibited by non-toxic doses of antimycin A1. Hypoxia inducible factor (HIF)-1alpha protein levels were significantly decreased by antimycin A1, but its mRNA level was not affected. Antimycin A1 is known to be an inhibitor of mitochondrial electron transport system, and depletion of mitochondria abolished antimycin A1-effect, at least in part. Inhibitors of proteasome or protein synthesis did not affect the decrease in HIF-1alpha level induced by antimycin A1. These results indicate that antimycin A1 inhibited angiogenesis through decrease in VEGF production caused by inhibition of HIF-1alpha activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.29.1344DOI Listing
July 2006

Dynamic statistical parametric mapping for analyzing the magnetoencephalographic epileptiform activity in patients with epilepsy.

J Child Neurol 2005 Apr;20(4):363-9

MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA.

Our current purpose is to evaluate the applicability of dynamic statistical parametric mapping, a novel method for localizing epileptiform activity recorded with magnetoencephalography in patients with epilepsy. We report four pediatric patients with focal epilepsies. Magnetoencephalographic data were collected with a 306-channel whole-head helmet-shaped sensor array. We calculated equivalent current dipoles and dynamic statistical parametric mapping movies of the interictal epileptiform discharges that were based in the minimum-L2 norm estimate, minimizing the square sum of the dipole element amplitudes. The dynamic statistical parametric mapping analysis of interictal epileptiform discharges can demonstrate the rapid change and propagation of interical epileptiform discharges. According to these findings, specific epileptogenic lesion-focal cortical dysplasia could be found and patients could be operated on successfully. The presurgical analysis of interictal epileptiform discharges using dynamic statistical parametric mapping seems to be promising in patients with a possible underlying focal cortical dysplasia and might help to guide the placement of invasive electrodes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/08830738050200041601DOI Listing
April 2005

Specific inhibition of hypoxia-inducible factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids.

Biol Pharm Bull 2003 Oct;26(10):1379-83

Department of Microbiology, Showa University of Pharmaceutical Sciences, Tokyo, Japan.

Screening using a reporter under the control of the hypoxia-response element (HRE) identified several flavonoids and homoisoflavonoids that inhibit the activation of HRE under hypoxic conditions. Among various compounds, isorhamnetin, luteolin, quercetin, and methyl ophiopogonanone B (MOB) were effective at 3 to 9 microg/ml in inhibiting the reporter activity. The expression of vascular endothelial growth factor (VEGF) mRNA during hypoxia was also inhibited by MOB in HepG2 cells, but the effective doses were 10 to 20 microg/ml. MOB caused destabilization of hypoxia-inducible factor (HIF)-1alpha, as revealed by Western blotting, that was dependent on proteasome activity and the tumor suppressor, p53. The tubular formation and migration of human umbilical vein endothelial cells was also inhibited by MOB. MOB is expected to act as an inhibitor of angiogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.26.1379DOI Listing
October 2003

HIF-1-dependent VEGF reporter gene assay by a stable transformant of CHO cells.

Biol Pharm Bull 2003 Apr;26(4):417-20

Institute of Microbial Chemistry, Tokyo, Japan.

For the establishment of a screening system to detect inhibitors of vascular endotherial growth factor (VEGF) expression, a stable transformant of Chinese hamster ovary cells was isolated and cloned by transfection of a hypoxia-inducible factor 1 (HIF-1)-dependent VEGF promoter reporter gene. The expression of the reporter gene in the clone cells, as measured by luciferase activity, was stable. Hypoxic responses were best observed at an initial cell density of 2 x 10(4)/well. The maximal increase of luciferase activity was 30 fold. In the highest cell density of 8 x 10(4)/well (2.1 x 10(5)/cm(2)), basal activity was increased 13-15 fold compared to that at the lower cell densities, and did not respond to hypoxia. Addition of CoCl(2), which is known to mimic hypoxia, increased luciferase activity more than 10 times in normoxia. Nitric oxide donors, which are known to suppress the activation of HIF-1, inhibited expression of the VEGF promoter reporter gene under hypoxia. Histone deacetylase inhibitors, trichostatin A and sodium n-butyrate which are known to stimulate transcription of many genes enhanced its transcription in hypoxia. These results indicate that the stable transformant is a useful tool for screening of HIF-1 modifiers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.26.417DOI Listing
April 2003

Induction of p16/INK4a gene expression and cellular senescence by toyocamycin.

Biol Pharm Bull 2002 Oct;25(10):1272-6

Department of Microbiology, Showa University School of Pharmaceutical Sciences Tokyo, Japan.

We constructed an assay system of a luciferase reporter with p16/lNK4a gene transcriptional regulatory domain to identify p16-inducing substances, and found toyocamycin to induce gene expression from the screening of culture fluids of Streptomyces. Toyocamycin is a nucleoside analog, and it increased the p16 mRNA level in human normal fibroblasts or synovial cells as assessed by Northern blot hybridization or real time RT-PCR. It also induced cellular senescence in normal human fibroblasts. The transcriptional regulatory regions of human p16 gene that were responsible for the induction were analyzed using deletion mutants of the transcriptional regulatory region of p16 linked to the luciferase gene. The DNA fragment -111 to +1 bp from the cap site was sufficient to drive toyocamycin-activated transcription of p16/luciferase reporter. Nucleotide sequences within this domain contained the Sp1- and Ets-binding sequences. Mutations were introduced into these sequences, and the Sp1 sequence was found to be critical for the induction, and this notion was confirmed from gel-mobility shift assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.25.1272DOI Listing
October 2002
-->