SGK1.1 Reduces Kainic Acid-Induced Seizure Severity and Leads to Rapid Termination of Seizures

2019 ◽  
Vol 30 (5) ◽  
pp. 3184-3197 ◽  
Author(s):  
Natalia Armas-Capote ◽  
Laura E Maglio ◽  
Leonel Pérez-Atencio ◽  
Elva Martin-Batista ◽  
Antonio Reboreda ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Neuronal Damage ◽  
Sympathetic Neurons ◽  
Active Form ◽  
Brain Slices ◽  
Dependent Manner ◽  
Seizure Severity ◽  
M Current ◽  
Electrophysiological Measurements

Abstract Approaches to control epilepsy, one of the most important idiopathic brain disorders, are of great importance for public health. We have previously shown that in sympathetic neurons the neuronal isoform of the serum and glucocorticoid-regulated kinase (SGK1.1) increases the M-current, a well-known target for seizure control. The effect of SGK1.1 activation on kainate-induced seizures and neuronal excitability was studied in transgenic mice that express a permanently active form of the kinase, using electroencephalogram recordings and electrophysiological measurements in hippocampal brain slices. Our results demonstrate that SGK1.1 activation leads to reduced seizure severity and lower mortality rates following status epilepticus, in an M-current–dependent manner. EEG is characterized by reduced number, shorter duration, and early termination of kainate-induced seizures in the hippocampus and cortex. Hippocampal neurons show decreased excitability associated to increased M-current, without altering basal synaptic transmission or other neuronal properties. Altogether, our results reveal a novel and selective anticonvulsant pathway that promptly terminates seizures, suggesting that SGK1.1 activation can be a potent factor to secure the brain against permanent neuronal damage associated to epilepsy.

The Anticonvulsant Drug Retigabine Enhances M-current and Reduces Neuronal Excitability in Bullfrog Sympathetic Neurons

BIOS ◽  
2010 ◽  
Vol 81 (2) ◽  
pp. 55-61
Author(s):  
Rebecca Riblet ◽  
Amanpreet Kaur ◽  
Harleen Kaur ◽  
Mark D. Womble
Keyword(s):  
Neuronal Excitability ◽  
Sympathetic Neurons ◽  
Anticonvulsant Drug ◽  
M Current

scholarly journals Formin Activity and mDia1 Contribute to Maintain Axon Initial Segment Composition and Structure

2021 ◽  
Author(s):  
Wei Zhang ◽  
María Ciorraga ◽  
Pablo Mendez ◽  
Diana Retana ◽  
Norah Boumedine-Guignon ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Initial Segment ◽  
Protein Transport ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
Axon Initial Segment ◽  
Composition And Structure ◽  
The Stability ◽  
Protein Density ◽  
Voltage Gated Ion Channels

AbstractThe axon initial segment (AIS) is essential for maintaining neuronal polarity, modulating protein transport into the axon, and action potential generation. These functions are supported by a distinctive actin and microtubule cytoskeleton that controls axonal trafficking and maintains a high density of voltage-gated ion channels linked by scaffold proteins to the AIS cytoskeleton. However, our knowledge of the mechanisms and proteins involved in AIS cytoskeleton regulation to maintain or modulate AIS structure is limited. In this context, formins play a significant role in the modulation of actin and microtubules. We show that pharmacological inhibition of formins modifies AIS actin and microtubule characteristics in cultured hippocampal neurons, reducing F-actin density and decreasing microtubule acetylation. Moreover, formin inhibition diminishes sodium channels, ankyrinG and βIV-spectrin AIS density, and AIS length, in cultured neurons and brain slices, accompanied by decreased neuronal excitability. We show that genetic downregulation of the mDia1 formin by interference RNAs also decreases AIS protein density and shortens AIS length. The ankyrinG decrease and AIS shortening observed in pharmacologically inhibited neurons and neuron-expressing mDia1 shRNAs were impaired by HDAC6 downregulation or EB1-GFP expression, known to increase microtubule acetylation or stability. However, actin stabilization only partially prevented AIS shortening without affecting AIS protein density loss. These results suggest that mDia1 maintain AIS composition and length contributing to the stability of AIS microtubules.

scholarly journals The Anti-Tumor Agent Sodium Selenate Decreases Methylated PP2A, Increases GSK3βY216 Phosphorylation, Including Tau Disease Epitopes and Reduces Neuronal Excitability in SHSY-5Y Neurons

2019 ◽  
Vol 20 (4) ◽  
pp. 844 ◽  
Author(s):  
Wesal Habbab ◽  
Imad Aoudé ◽  
Freshteh Palangi ◽  
Sara Abdulla ◽  
Tariq Ahmed
Keyword(s):  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Active Form ◽  
Close Correlation ◽  
Maximum Effect ◽  
Sodium Selenate ◽  
Dependent Manner ◽  
Maximum Increase ◽  
Electrophysiological Studies ◽  
Catalytically Active

Selenium application as sodium selenate was repeatedly shown to have anti-carcinogenic properties by increasing levels of the serine/ threonine protein phosphatase 2A (PP2A) in cancer cells. PP2A has a prominent role in cell development, homeostasis, and in neurons regulates excitability. PP2A, GSK3β and Tau reside together in a complex, which facilitates their interaction and (dys)-function as has been reported for several neurological disorders. In this study we recorded maximum increase in total PP2A at 3 µM sodium selenate in a neuron cell line. In conjunction with these data, whole-cell electrophysiological studies revealed that this concentration had maximum effect on membrane potentials, conductance and currents. Somewhat surprisingly, the catalytically active form, methylated PP2A (mePP2A) was significantly decreased. In close correlation to these data, the phosphorylation state of two substrate proteins, sensitive to PP2A activity, GSK3β and Tau were found to be increased. In summary, our data reveal that sodium selenate enhances PP2A levels, but reduces catalytic activity of PP2A in a dose dependent manner, which fails to reduce Tau and GSK3β phosphorylation under physiological conditions, indicating an alternative route in the rescue of cell pathology in neurological disorders.

scholarly journals Anticonvulsant effect of dipropofol by enhancing native GABA currents in cortical neurons in mice

2018 ◽  
Vol 120 (3) ◽  
pp. 1404-1414 ◽  
Author(s):  
Jingliang Zhang ◽  
Xiaoling Chen ◽  
Matti Kårbø ◽  
Yi Zhao ◽  
Long An ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Mouse Model ◽  
Kainic Acid ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
Anticonvulsant Effect ◽  
Dependent Manner ◽  
Whole Cell ◽  
Whole Cell Patch Clamp ◽  
Dose Dependent

Temporal lobe epilepsy (TLE), the most common pharmacoresistant focal epilepsy disorder, remains a major unmet medical need. Propofol is used as a short-acting medication for general anesthesia and refractory status epilepticus with issues of decreased consciousness and memory loss. Dipropofol, a derivative of propofol, has been reported to exert antioxidative and antibacterial activities. Here we report that dipropofol exerted anticonvulsant activity in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices from the medial entorhinal cortex (mEC) revealed that dipropofol hyperpolarized the resting membrane potential and reduced the number of action potential firings, resulting in suppression of cortical neuronal excitability. Furthermore, dipropofol activated native tonic GABAA currents of mEC layer II stellate neurons in a dose-dependent manner with an EC50 value of 9.3 ± 1.6 μM (mean ± SE). Taken together, our findings show that dipropofol activated GABAA currents and exerted anticonvulsant activities in mice, thus possessing developmental potential for new anticonvulsant therapy. NEW & NOTEWORTHY The anticonvulsant effect of dipropofol was shown in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices showed suppression of cortical neuronal excitability by dipropofol. Dipropofol activated the native tonic GABAA currents in a dose-dependent manner.

Volatile Anesthetics Increase Intracellular Calcium in Cerebrocortical and Hippocampal Neurons 

1999 ◽  
Vol 90 (4) ◽  
pp. 1137-1145 ◽  
Author(s):  
Christoph H. Kindler ◽  
Helge Eilers ◽  
Paul Donohoe ◽  
Surhan Ozer ◽  
Philip E. Bickler
Keyword(s):  
Intracellular Calcium ◽  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Free Medium ◽  
Ca1 Neurons

Background An increase in intracellular calcium concentration ([Ca2+]i) in neurons has been proposed as an important effect of volatile anesthetics, because they alter signaling pathways that influence neurotransmission. However, the existing data for anesthetic-induced increases in [Ca2+]i conflict. Methods Changes in [Ca2+]i were measured using fura-2 fluorescence spectroscopy in rat cortical brain slices at 90, 185, 370, and 705 microM isoflurane. To define the causes of an increase in [Ca2+]i, slices were studied in Ca2+-free medium, in the presence of Ca2+-channel blockers, and in the presence of the Ca2+-release inhibitor azumolene. The authors compared the effect of the volatile anesthetic with that of the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane. Single-dose experiments in CA1 neurons in hippocampal slices with halothane (360 microM) and in acutely dissociated CA1 neurons with halothane (360 microM) and isoflurane (445 microM) also were performed. Results Isoflurane at 0.5, 1, and 2 minimum alveolar concentrations increased basal [Ca2+]i in cortical slices in a dose-dependent manner (P < 0.05). This increase was not altered by Ca2+-channel blockers or Ca2+-free medium but was reduced 85% by azumolene. The nonanesthetic 1,2-dichlorohexafluorocyclobutane did not increase [Ca2+]i. In dissociated CA1 neurons, isoflurane reversibly increased basal [Ca2+]i by 15 nM (P < 0.05). Halothane increased [Ca2+]i in dissociated CA1 neurons and CA1 neurons in hippocampal slices by approximately 30 nM (P < 0.05). Conclusions (1) Isoflurane and halothane reversibly increase [Ca2+]i in isolated neurons and in neurons within brain slices. (2) The increase in [Ca2+]i is caused primarily by release from intracellular stores. (3) Increases in [Ca2+]i occur with anesthetics but not with the nonanesthetic 1,2-dichlorohexafluorocyclobutane.

scholarly journals Neurons, Receptors, and Channels

2020 ◽  
Vol 60 (1) ◽  
pp. 9-30 ◽  
Author(s):  
David A. Brown
Keyword(s):  
Messenger Rna ◽  
Neuronal Excitability ◽  
Single Channel ◽  
Sympathetic Neurons ◽  
Electrophysiological Recording ◽  
Muscarinic Agonists ◽  
M Current ◽  
Antisense Knockdown ◽  
Sympathetic Transmission ◽  
Laboratory Life

Here, I recount some adventures that I and my colleagues have had over some 60 years since 1957 studying the effects of drugs and neurotransmitters on neuronal excitability and ion channel function, largely, but not exclusively, using sympathetic neurons as test objects. Studies include effects of centrally active drugs on sympathetic transmission; neuronal action and neuroglial uptake of GABA in the ganglia and brain; the action of muscarinic agonists on sympathetic neurons; the action of bradykinin on neuroblastoma-derived cells; and the identification of M-current as a target for muscarinic action, including experiments to determine its distribution, molecular composition, neurotransmitter sensitivity, and intracellular regulation by phospholipids and their hydrolysis products. Techniques used include electrophysiological recording (extracellular, intracellular microelectrode, whole-cell, and single-channel patch-clamp), autoradiography, messenger RNA and complementary DNA expression, antibody injection, antisense knockdown, and membrane-targeted lipidated peptides. I finish with some recollections about my scientific career, funding, and changes in laboratory life and pharmacology research over the past 60 years.

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

2015 ◽  
Vol 113 (5) ◽  
pp. 1493-1500 ◽  
Author(s):  
Hoyong Park ◽  
Sungmin Kim ◽  
Jeehae Rhee ◽  
Hyeon-Joong Kim ◽  
Jung-Soo Han ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Lysophosphatidic Acid ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Receptor Activation ◽  
Cell System ◽  
Adult Brain ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Central Synapses

Lysophosphatidic acid (LPA) is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca2+ in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases.

scholarly journals SGK1.1 activation causes early seizure termination via effects on M-current

2019 ◽  
Author(s):  
Natalia Armas-Capote ◽  
Laura E. Maglio ◽  
Leonel Pérez-Atencio ◽  
Elva Martin-Batista ◽  
Antonio Reboreda ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Neuronal Excitability ◽  
Active Form ◽  
Cellular Level ◽  
Adverse Outcomes ◽  
Early Termination ◽  
Ca1 Neurons ◽  
M Current ◽  
Acute Seizures ◽  
Hippocampal Ca1

AbstractEarly termination of status epilepticus affords protection against brain damage and associated pathologies. Regulation of Kv7.2/7.3 potassium channels, underlying the neuronal M-current, is key for seizure control. This conductance is maintained during initiation of action potentials, affecting neuronal excitability and thus inhibiting epileptic discharges. The M-current is upregulated by the neuronal isoform of the serum and glucocorticoid-regulated kinase SGK1 (SGK1.1). We tested whether SGK1.1 is an anticonvulsant factor using the kainic acid (KA) model of acute seizures in a transgenic mouse model with expression of a constitutively active form of the kinase. Our results demonstrate that SGK1.1 confers robust protection against seizures associated to lower mortality levels, independently of sex or genetic background. SGK1.1-dependent protection results in reduced number, shorter duration, and early termination of EEG seizures. At the cellular level, it is associated to increased M-current amplitude mediated by Nedd4-2 phosphorylation, leading to decreased excitability of hippocampal CA1 neurons without alteration of basal synaptic transmission. Altogether, our results reveal that SGK1.1-mediated M-current upregulation in the hippocampus is a key component of seizure resistance in the KA epileptic paradigm, suggesting that regulation of this anticonvulsant pathway may improve adverse outcomes to status epilepticus, constituting a potential target for antiepileptic drugs.

scholarly journals Ethanol Elevates Excitability of Superior Cervical Ganglion Neurons by Inhibiting Kv7 Channels in a Cell Type-Specific and PI(4,5)P2-Dependent Manner

2019 ◽  
Vol 20 (18) ◽  
pp. 4419 ◽  
Author(s):  
Kwon-Woo Kim ◽  
Keetae Kim ◽  
Hyosang Lee ◽  
Byung-Chang Suh
Keyword(s):  
Membrane Potential ◽  
Superior Cervical Ganglion ◽  
Neuronal Excitability ◽  
Sympathetic Neurons ◽  
Expression System ◽  
Dependent Manner ◽  
Cellular Targets ◽  
Kv7 Channels ◽  
Cervical Ganglion ◽  
Ganglion Neurons

Alcohol causes diverse acute and chronic symptoms that often lead to critical health problems. Exposure to ethanol alters the activities of sympathetic neurons that control the muscles, eyes, and blood vessels in the brain. Although recent studies have revealed the cellular targets of ethanol, such as ion channels, the molecular mechanism by which alcohol modulates the excitability of sympathetic neurons has not been determined. Here, we demonstrated that ethanol increased the discharge of membrane potentials in sympathetic neurons by inhibiting the M-type or Kv7 channel consisting of the Kv7.2/7.3 subunits, which were involved in determining the membrane potential and excitability of neurons. Three types of sympathetic neurons, classified by their threshold of activation and firing patterns, displayed distinct sensitivities to ethanol, which were negatively correlated with the size of the Kv7 current that differs depending on the type of neuron. Using a heterologous expression system, we further revealed that the inhibitory effects of ethanol on Kv7.2/7.3 currents were facilitated or diminished by adjusting the amount of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). These results suggested that ethanol and PI(4,5)P2 modulated gating of the Kv7 channel in superior cervical ganglion neurons in an antagonistic manner, leading to regulation of the membrane potential and neuronal excitability, as well as the physiological functions mediated by sympathetic neurons.

scholarly journals Protective Effect of Apoptosis-Inhibitory Agent, N-Tosyl-l-Phenylalanyl Chloromethyl Ketone against Ischemia-Induced Hippocampal Neuronal Damage

1998 ◽  
Vol 18 (8) ◽  
pp. 819-823 ◽  
Author(s):  
Akira Hara ◽  
Masayuki Niwa ◽  
Masaya Nakashima ◽  
Tomohiko Iwai ◽  
Toshihiko Uematsu ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Hippocampal Neurons ◽  
Therapeutic Strategy ◽  
Neuronal Damage ◽  
Dependent Manner ◽  
Chloromethyl Ketone ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 ◽  
Dose Dependent ◽  
Hippocampal Ca1 Sector

Delayed neuronal death in the gerbil hippocampal CA1 sector occurs 48 to 72 hours after severe forebrain ischemia. DNA fragmentation is observed in the hippocampal CA1 neurons at around that time. We show here that an inhibitor of proteolytic process of apoptosis, N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK), protected hippocampal neuronal damage by inhibition of the DNA fragmentation in a dose-dependent manner and that TPCK induced an apoptosis-regulating molecule, Bcl-2 protein, in the surviving neurons. These results suggest the prevention of apoptosis-related DNA fragmentation by TPCK may be an attractive therapeutic strategy for preserving hippocampal neurons from ischemic insult.

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