scholarly journals Dysregulation of REV-ERBα impairs GABAergic function and promotes epileptic seizures in preclinical models

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tianpeng Zhang ◽  
Fangjun Yu ◽  
Haiman Xu ◽  
Min Chen ◽  
Xun Chen ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Epileptic Seizures ◽  
Synaptic Function ◽  
Preclinical Models ◽  
Pharmacological Modulation ◽  
Mouse Hippocampus ◽  
Elevated Frequency ◽  
Patients With Epilepsy ◽  
Gabaergic Function

AbstractTo design potentially more effective therapies, we need to further understand the mechanisms underlying epilepsy. Here, we uncover the role of Rev-erbα in circadian regulation of epileptic seizures. We first show up-regulation of REV-ERBα/Rev-erbα in brain tissues from patients with epilepsy and a mouse model. Ablation or pharmacological modulation of Rev-erbα in mice decreases the susceptibility to acute and chronic seizures, and abolishes diurnal rhythmicity in seizure severity, whereas activation of Rev-erbα increases the animal susceptibility. Rev-erbα ablation or antagonism also leads to prolonged spontaneous inhibitory postsynaptic currents and elevated frequency in the mouse hippocampus, indicating enhanced GABAergic signaling. We also identify the transporters Slc6a1 and Slc6a11 as regulators of Rev-erbα-mediated clearance of GABA. Mechanistically, Rev-erbα promotes the expressions of Slc6a1 and Slc6a11 through transcriptional repression of E4bp4. Our findings propose Rev-erbα as a regulator of synaptic function at the crosstalk between pathways regulating the circadian clock and epilepsy.

scholarly journals Epileptic trances – focal motor epileptic seizures: past, present and a little bit of future

2019 ◽  
Vol 13 (4) ◽  
pp. 64-69
Author(s):  
V. A. Chadaev ◽  
K. Yu. Mukhin ◽  
L. G. Selezneva ◽  
S. R. Nurmukhametova ◽  
A. A. Alikhanov ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Surgical Treatment ◽  
Diagnostic Algorithm ◽  
Epileptic Seizures ◽  
Rare Type ◽  
Patients With Epilepsy ◽  
Legal Expertise

This article provides a detailed description of clinical and electroanatomical characteristics of epilepsy in patients suffering from epileptic trances – a rare type of focal motor seizures with ambulatory automatism manifesting as an unplanned travel. We reviewed the currently available data on the nature of psychical seizures in patients with epilepsy and the role of social and legal expertise for this disease. We developed the criteria for differential diagnosis between epileptic trances and other conditions with similar manifestations (for example, epileptic fugues) and identified a diagnostic minimum. We also proposed a hypothesis of ictal spatial migration. We emphasized the efficiency of surgical treatment in the case of compliance with a proper diagnostic algorithm.

scholarly journals P.037 Role of epilepsy monitoring unit in the investigation of patients with epilepsy and developmental delay

2017 ◽  
Vol 44 (S2) ◽  
pp. S23-S23
Author(s):  
A Suller Marti ◽  
S Mirsattari ◽  
M Aldosari ◽  
K Ikeda ◽  
W Huang
Keyword(s):  
Developmental Delay ◽  
Focal Epilepsy ◽  
Epileptic Seizures ◽  
Increased Risk ◽  
The Mean ◽  
Drug Resistant Epilepsy ◽  
Patients With Epilepsy ◽  
Epilepsy Monitoring

Background: A significant part of the developmental delay (DD) population has epilepsy (26-70%) and live in an institution. These patients tend to have atypical presentation of epileptic seizures with higher risk of misdiagnosis. Distinguishing their ictal events from paroxysmal behaviors can be challenging.There often is a lack of description of the spells or inadequate history from the caregivers or the patients. These patients often have drug resistant epilepsy requiring polypharmacy with increased risk of morbidity and mortality. The aim of this study was to determine usefulness of Epilepsy Monitoring Unit (EMU) in diagnosis and management of these patients. Methods: This is a retrospective observational study of the patients with epilepsy and DD living in institutions that were admitted to the EMU. Results: Four patients met the inclusion criteria for this study. The mean age was 45(29-71), 3/4 (N=3) were male and 3/4 had focal epilepsy. All patients had mood disorders and 2 were taking antipsychotic medication. The mean admission-time was 6,25 days(2-15) and there was a correlation with the events and seizures in 2/4 of the patients and the rest had a combination of behavioural-changes and seizures. Conclusions: EMU admission can provide an accurate diagnosis of spells in patients with DD and epilepsy, and improve their quality of life.

The use of progesterone during pregnancy in women with epilepsy as an alternative to the correction of doses of anticonvulsants

GYNECOLOGY ◽  
2020 ◽  
Vol 21 (6) ◽  
pp. 12-15
Author(s):  
Elena V. Tsallagova ◽  
Vasily O. Generalov ◽  
Timur R. Sadykov
Keyword(s):  
Clinical Remission ◽  
Epileptic Seizures ◽  
Progesterone Concentration ◽  
Teratogenic Effects ◽  
Safe Alternative ◽  
Patients With Epilepsy

Pregnancy is the most dangerous period in terms of interruption of even persistent and long-term remission. At the same time increasing the dose of anticonvulsant increases the risk of teratogenic effects. Aim. to assess the possibility of using progesterone to prevent relapse of epileptic seizures during pregnancy. Materials and methods. 38 pregnant patients with epilepsy with clinical remission before pregnancy, with relapse of epileptic seizures in I trimester of pregnancy, age 31.81.4 years. Dydrogesterone in a dose of 10 to 60 mg/day was prescribed after the relapse of remission. Anticonvulsant dosage was not changed. The blood progesterone concentration and EEG control was carried out. Results. During pregnancy, the level of progesterone in the blood gradually increased from 77.8 nmol/l at 78 weeks of pregnancy to 521.1 nmol/l at 3637 weeks of pregnancy, without exceeding the limits. EEG results did not deteriorate. None of the patients had seizures during pregnancy. Conclusion. Progesterone therapy is an adequate and safe alternative to increasing the dose of anticonvulsants in case of recurrent seizures during pregnancy.

scholarly journals Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation

2021 ◽  
Vol 22 (7) ◽  
pp. 3787
Author(s):  
Hussam Ibrahim ◽  
Philipp Reus ◽  
Anna Katharina Mundorf ◽  
Anna-Lena Grothoff ◽  
Valerie Rudenko ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Transcriptional Repression ◽  
Small Gtpase ◽  
Main Role ◽  
Interacting Proteins ◽  
Casein Kinase 1 ◽  
Bona Fide ◽  
Kinetics Of

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

scholarly journals Genetic Analysis of the Role of Pol II Holoenzyme Components in Repression by the Cyc8-Tup1 Corepressor in Yeast

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1535-1542 ◽  
Author(s):  
Mark Lee ◽  
Sukalyan Chatterjee ◽  
Kevin Struhl
Keyword(s):  
Transcriptional Repression ◽  
Detectable Effect ◽  
Genetic Screens ◽  
Phenotypic Analysis ◽  
Histone Tails ◽  
Pol Ii ◽  
Corepressor Complex ◽  
The Individual ◽  
Modest Effect

Abstract The Cyc8-Tup1 corepressor complex is targeted to promoters by pathway-specific DNA-binding repressors, thereby inhibiting the transcription of specific classes of genes. Genetic screens have identified mutations in a variety of Pol II holoenzyme components (Srb8, Srb9, Srb10, Srb11, Sin4, Rgr1, Rox3, and Hrs1) and in the N-terminal tails of histones H3 and H4 that weaken repression by Cyc8-Tup1. Here, we analyze the effect of individual and multiple mutations in many of these components on transcriptional repression of natural promoters that are regulated by Cyc8-Tup1. In all cases tested, individual mutations have a very modest effect on SUC2 RNA levels and no detectable effect on levels of ANB1, MFA2, and RNR2. Furthermore, multiple mutations within the Srb components, between Srbs and Sin4, and between Srbs and histone tails affect Cyc8-Tup1 repression to the same modest extent as the individual mutations. These results argue that the weak effects of the various mutations on repression by Cyc8-Tup1 are not due to redundancy among components of the Pol II machinery, and they argue against a simple redundancy between the holoenzyme and chromatin pathways. In addition, phenotypic analysis indicates that, although Srbs8–11 are indistinguishable with respect to Cyc8-Tup1 repression, the individual Srbs are functionally distinct in other respects. Genetic interactions among srb mutations imply that a balance between the activities of Srb8 + Srb10 and Srb11 is important for normal cell growth.

scholarly journals Perception about Etiology of Epilepsy and Help-Seeking Behavior in Patients with Epilepsy

2021 ◽  
Author(s):  
Gautam Das ◽  
Samar Biswas ◽  
Souvik Dubey ◽  
Durjoy Lahiri ◽  
Biman Kanti Ray ◽  
...  
Keyword(s):  
Help Seeking ◽  
Tertiary Care ◽  
Epileptic Seizures ◽  
Treatment Seeking ◽  
Professional Help ◽  
Epileptic Patients ◽  
Seeking Behavior ◽  
Tertiary Care Centers ◽  
Patients With Epilepsy

Abstract Objectives Patients with epilepsy and their family have diverse beliefs about the cause of their illness that generally determine their treatment-seeking behavior. In this study, our aim was to find out different beliefs about epilepsy that lead to different help-seeking patterns, which act as barrier to the intended modern medical management of epilepsy. Materials and Methods One hundred and fifty consecutive consenting patients accompanied by a reliable informant/family member fulfilling the International Classification of Epileptic Seizures (ICES), simplified version, were included. Demographic and clinical data of all the eligible subjects was collected. Perceived cause of illness and help-seeking pattern were explored from patient/informant by administering proper instruments. Results Respondents identified varied causes of epilepsy and explored multiple help-seeking options before reaching tertiary care centers. We observed that, generally, epileptic patients/relatives who had belief in causes like supernatural causes sought help from nonprofessional personnel and those attributed their symptom to bodily pathology had professional help-seeking. Conclusions The belief in supernatural causes not being conformed to the biomedical models of the epileptic disorders increases the treatment gap.

scholarly journals Ndufs4 ablation decreases synaptophysin expression in hippocampus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Subrata Kumar Shil ◽  
Yoshiteru Kagawa ◽  
Banlanjo Abdulaziz Umaru ◽  
Fumika Nanto-Hara ◽  
Hirofumi Miyazaki ◽  
...  
Keyword(s):  
Nadh Dehydrogenase ◽  
Leigh Syndrome ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Activity ◽  
Mitochondrial Complex ◽  
Neuronal Function ◽  
Mouse Hippocampus ◽  
Extracellular Regulated Kinase ◽  
Presynaptic Protein

AbstractAltered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.

scholarly journals Stoichiometric Analysis of Shifting in Subcellular Compartmentalization of HSP70 within Ischemic Penumbra

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3578
Author(s):  
Federica Mastroiacovo ◽  
Francesca Biagioni ◽  
Paola Lenzi ◽  
Larisa Ryskalin ◽  
Stefano Puglisi-Allegra ◽  
...  
Keyword(s):  
Direct Evidence ◽  
Neuronal Survival ◽  
Hsp 70 ◽  
Preclinical Models ◽  
Brain Areas ◽  
Cell Compartments ◽  
Control Brain ◽  
Disease Modifier ◽  
Subcellular Compartmentalization

The heat shock protein (HSP) 70 is considered the main hallmark in preclinical studies to stain the peri-infarct region defined area penumbra in preclinical models of brain ischemia. This protein is also considered as a potential disease modifier, which may improve the outcome of ischemic damage. In fact, the molecule HSP70 acts as a chaperonine being able to impact at several level the homeostasis of neurons. Despite being used routinely to stain area penumbra in light microscopy, the subcellular placement of this protein within area penumbra neurons, to our knowledge, remains undefined. This is key mostly when considering studies aimed at deciphering the functional role of this protein as a determinant of neuronal survival. The general subcellular placement of HSP70 was grossly reported in studies using confocal microscopy, although no direct visualization of this molecule at electron microscopy was carried out. The present study aims to provide a direct evidence of HSP70 within various subcellular compartments. In detail, by using ultrastructural morphometry to quantify HSP70 stoichiometrically detected by immuno-gold within specific organelles we could compare the compartmentalization of the molecule within area penumbra compared with control brain areas. The study indicates that two cell compartments in control conditions own a high density of HSP70, cytosolic vacuoles and mitochondria. In these organelles, HSP70 is present in amount exceeding several-fold the presence in the cytosol. Remarkably, within area penumbra a loss of such a specific polarization is documented. This leads to the depletion of HSP70 from mitochondria and mostly cell vacuoles. Such an effect is expected to lead to significant variations in the ability of HSP70 to exert its physiological roles. The present findings, beyond defining the neuronal compartmentalization of HSP70 within area penumbra may lead to a better comprehension of its beneficial/detrimental role in promoting neuronal survival.

scholarly journals Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Barbara Jana ◽  
Jarosław Całka
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Domestic Animals ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Beta Adrenergic Receptor ◽  
Pharmacological Modulation ◽  
Uterine Inflammation ◽  
Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

scholarly journals Emerging multifaceted roles of BAP1 complexes in biological processes

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Aileen Patricia Szczepanski ◽  
Lu Wang
Keyword(s):  
Transcriptional Repression ◽  
Target Genes ◽  
Regulatory Mechanisms ◽  
Biological Processes ◽  
Multiprotein Complex ◽  
Downstream Target ◽  
Evolutionarily Conserved ◽  
Complex Forms ◽  
Polycomb Repressive Complex 1

AbstractHistone H2AK119 mono-ubiquitination (H2AK119Ub) is a relatively abundant histone modification, mainly catalyzed by the Polycomb Repressive Complex 1 (PRC1) to regulate Polycomb-mediated transcriptional repression of downstream target genes. Consequently, H2AK119Ub can also be dynamically reversed by the BAP1 complex, an evolutionarily conserved multiprotein complex that functions as a general transcriptional activator. In previous studies, it has been reported that the BAP1 complex consists of important biological roles in development, metabolism, and cancer. However, identifying the BAP1 complex’s regulatory mechanisms remains to be elucidated due to its various complex forms and its ability to target non-histone substrates. In this review, we will summarize recent findings that have contributed to the diverse functional role of the BAP1 complex and further discuss the potential in targeting BAP1 for therapeutic use.

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