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Full-Text Articles in Medical Neurobiology
Anticonvulsant Potencies Of The Enantiomers Of The Neurosteroids Androsterone And Etiocholanolone Exceed Those Of The Natural Forms, Dorota Zolkowska, Ashish Dhir, Kathiresan Krishnan, Douglas F. Covey, Michael A. Rogawski
Anticonvulsant Potencies Of The Enantiomers Of The Neurosteroids Androsterone And Etiocholanolone Exceed Those Of The Natural Forms, Dorota Zolkowska, Ashish Dhir, Kathiresan Krishnan, Douglas F. Covey, Michael A. Rogawski
Michael A. Rogawski
RATIONALE: Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABA-A receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABA-A receptors than the natural forms. OBJECTIVES: The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models. METHODS: Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 …
Adjunctive Perampanel For Refractory Partial-Onset Seizures. Randomized Phase Iii Study 304, Jacqueline A. French, Gregory L. Krauss, Victor Biton, David Squillacote, Haichen Yang, Antonio Laurenza, Dinesh Kumar, Michael A. Rogawski
Adjunctive Perampanel For Refractory Partial-Onset Seizures. Randomized Phase Iii Study 304, Jacqueline A. French, Gregory L. Krauss, Victor Biton, David Squillacote, Haichen Yang, Antonio Laurenza, Dinesh Kumar, Michael A. Rogawski
Michael A. Rogawski
Objective: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures. Methods:This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (≥12 years, with ongoing seizures despite 1–3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder …
Characterization Of Seizures Induced By Acute And Repeated Exposure To Tetramethylenedisulfotetramine, Dorota Zolkowska, Christopher N. Banks, Ashish Dhir, Bora Inceoglu, James R. Sanborn, Mark R. Mccoy, Donald A. Bruun, Bruce D. Hammock, Pamela J. Lein, Michael A. Rogawski
Characterization Of Seizures Induced By Acute And Repeated Exposure To Tetramethylenedisulfotetramine, Dorota Zolkowska, Christopher N. Banks, Ashish Dhir, Bora Inceoglu, James R. Sanborn, Mark R. Mccoy, Donald A. Bruun, Bruce D. Hammock, Pamela J. Lein, Michael A. Rogawski
Michael A. Rogawski
Tetramethylenedisulfotetramine (tetramine; TETS) is a potent convulsant poison that is considered to be a chemical threat agent. To provide a basis for the investigation of antidotes for TETS-induced seizures, we characterized the convulsant activity of TETS in mice and rats when administered by the intraperitoneal, intravenous, oral and intraventricular routes as a single acute dose and with repeated sublethal doses. In mice, parenteral and oral TETS caused immobility, myoclonic body jerks, clonic seizures of the forelimbs and/or hindlimbs, tonic seizures and death. The CD50 values for clonic and tonic seizures following oral administration were 0.11 and 0.22 mg/kg, respectively. Intraventricular …
Role Of Neurosteroids In The Anticonvulsant Activity Of Midazolam, Ashish Dhir, Michael A. Rogawski
Role Of Neurosteroids In The Anticonvulsant Activity Of Midazolam, Ashish Dhir, Michael A. Rogawski
Michael A. Rogawski
BACKGROUND AND PURPOSE Midazolam is a short-acting benzodiazepine that is widely used as an intravenous sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA-A receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA-A receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. EXPERIMENTAL APPROACH Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the intravenous pentylenetetrazol (PTZ) threshold test. KEY …
Propofol Hemisuccinate Suppresses Cortical Spreading Depression, Ashish Dhir, Christoph Lossin, Michael A. Rogawski
Propofol Hemisuccinate Suppresses Cortical Spreading Depression, Ashish Dhir, Christoph Lossin, Michael A. Rogawski
Michael A. Rogawski
Propofol is a rapidly acting water-insoluble non-barbiturate anesthetic agent that is widely used as an intravenous sedative-hypnotic agent. Anecdotal evidence indicates that propofol may be effective at terminating intractable migraine headache. Cortical spreading depression (CSD) is believed to be the neural correlate of migraine aura and may be a trigger for migraine pain. Agents that block the induction or slow the spread of CSD may be of utility in treating migraine. Here we examined the ability of propofol hemisuccinate (PHS), a water-soluble prodrug of propofol, to affect CSD in mice. For comparison, we examinined dizocilpine, an NMDA receptor antagonist, that …
11beta-Hydroxylase Inhibitors Protect Against Seizures In Mice By Increasing Endogenous Neurosteroid Synthesis, Rafal Kaminski, Michael Rogawski
11beta-Hydroxylase Inhibitors Protect Against Seizures In Mice By Increasing Endogenous Neurosteroid Synthesis, Rafal Kaminski, Michael Rogawski
Michael A. Rogawski
Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABA-A receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but …
Seizure Protection By Intrapulmonary Delivery Of Propofol Hemisuccinate, Ashish Dhir, Dorota Zolkowska, Randall B. Murphy, Michael A. Rogawski
Seizure Protection By Intrapulmonary Delivery Of Propofol Hemisuccinate, Ashish Dhir, Dorota Zolkowska, Randall B. Murphy, Michael A. Rogawski
Michael A. Rogawski
The lung provides a portal of entry for drug delivery that could be used to administer anticonvulsant substances to prevent or abort seizures. Here we demonstrate that intrapulmonary propofol hemisucinate (PHS) rapidly confers seizure protection in various rodent chemoconvulsant models. Propofol is a powerful anticonvulsant substance at subanesthetic doses but it is a viscous, water-immiscible oil that is not suitable for intrapulmonary administration. We found that PHS can be formulated as an aqueous solution that is well tolerated when instilled into the lung. High dose intraperitoneal PHS induced loss-of-righting reflex in rats and mice. The onset of action of PHS …
Ganaxolone Suppression Of Behavioral And Electrographic Seizures In The Mouse Amygdala Kindling Model, Doodipala S. Reddy, Michael A. Rogawski
Ganaxolone Suppression Of Behavioral And Electrographic Seizures In The Mouse Amygdala Kindling Model, Doodipala S. Reddy, Michael A. Rogawski
Michael A. Rogawski
Ganaxolone (3alpha-hydroxy-3alpha-methyl-5alpha-pregnan-20-one), a synthetic analog of the endogenous neurosteroid allopregnanolone and a positive allosteric modulator of GABA-A receptors, may represent a new treatment approach for epilepsy. Here we demonstrate that pretreatment with ganaxolone (1.25—20 mg/kg, s.c.) causes a dose-dependent suppression of behavioral and electrographic seizures in fully amygdala-kindled female mice, with nearly complete seizure protection at the highest dose tested. The ED50 for suppression of behavioral seizures was 6.6 mg/kg. The seizure suppression produced by ganaxolone was comparable to that of clonazepam (ED50, 0.1 mg/kg, s.c.). To the extent that amygdala kindling represents a model of mesial temporal lobe epilepsy, …
Treatment Of Early And Late Kainic-Acid Induced Status Epilepticus With The Non-Competitive Ampa Receptor Antagonist Gyki 52466, Brita Fritsch, Jeffrey J. Stott, J. Joelle Donofrio, Michael A. Rogawski
Treatment Of Early And Late Kainic-Acid Induced Status Epilepticus With The Non-Competitive Ampa Receptor Antagonist Gyki 52466, Brita Fritsch, Jeffrey J. Stott, J. Joelle Donofrio, Michael A. Rogawski
Michael A. Rogawski
Purpose: Benzodiazepines such as diazepam may fail to effectively treat status epilepticus because benzodiazepine-sensitive GABA-A receptors are internalized progressively with continued seizure activity. Ionotropic glutamate receptors, including AMPA receptors, are externalized, so that AMPA receptor antagonists, which are broad-spectrum anticonvulsants, could be more effective treatments for satus epilepticus. We assessed the ability of the non-competitive AMPA receptor antagonist GYKI 52466 to protect against kainic acid-induced status epilepticus in mice. Methods: Groups of animals treated with kainic acid received GYKI 52466 (50 mg/kg followed in 15 min by 50 mg/kg) or diazepam (25 mg/kg followed in 20 min by 12.5 mg/kg) …
Anticonvulsant And Proconvulsant Actions Of 2-Deoxy-D-Glucose, Maciej Gasior, Jessica Yankura, Adam L. Hartman, Amy French, Michael A. Rogawski
Anticonvulsant And Proconvulsant Actions Of 2-Deoxy-D-Glucose, Maciej Gasior, Jessica Yankura, Adam L. Hartman, Amy French, Michael A. Rogawski
Michael A. Rogawski
Purpose: 2-Deoxy-D-glucose (2-DG), a glucose analog that accumulates in cells and interferes with carbohydrate metabolism by inhibiting glycolytic enzymes, has anticonvulsant actions. Recognizing that severe glucose deprivation can induce seizures, we sought to determine whether acute treatment with 2-DG can promote seizure susceptibility by assessing its effects on seizure threshold. For comparison, we studied 3-methyl-glucose (3-MG), which like 2-DG accumulates in cells and reduces glucose uptake, but does not inhibit glycolysis. Methods: Mice were treated with 2-DG or 3-MG and the seizure threshold determined in the 6-Hz test, the mouse electroshock seizure threshold (MEST) test, and the intravenous pentylenetetrazol (i.v. …
Topiramate Reduces Excitability In The Basolateral Amygdala By Selectively Inhibiting Gluk1 (Glur5) Kainate Receptors On Interneurons And Positively Modulating Gaba-A Receptors On Principal Neurons, Maria Braga, Vassiliki Aroniadou-Anderjaska, He Li, Michael Rogawski
Topiramate Reduces Excitability In The Basolateral Amygdala By Selectively Inhibiting Gluk1 (Glur5) Kainate Receptors On Interneurons And Positively Modulating Gaba-A Receptors On Principal Neurons, Maria Braga, Vassiliki Aroniadou-Anderjaska, He Li, Michael Rogawski
Michael A. Rogawski
Topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] is a structurally novel antiepileptic drug that has broad efficacy in epilepsy, but the mechanisms underlying its therapeutic activity are not fully understood. We have found that topiramate selectively inhibits GluK1 (GluR5) kainate receptor-mediated excitatory postsynaptic responses in rat basolateral amygdala (BLA) principal neurons and protects against seizures induced by the GluK1 kainate receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA). Here, we demonstrate that topiramate also modulates inhibitory function in the BLA. Using whole-cell recordings in rat amygdala slices, we found that 0.3 to 10 microM topiramate 1) inhibited ATPA-evoked postsynaptic currents recorded from BLA interneurons; 2) suppressed ATPA-induced …
Pathological Alterations In Gabaergic Interneurons And Reduced Tonic Inhibition In The Basolateral Amygdala During Epileptogenesis, Michael A. Rogawski, Brita Fritsch, Felicia Qashu, T. H. Figueiredo, Vicki Aroniadou-Anderjaska, Maria F.M. Braga
Pathological Alterations In Gabaergic Interneurons And Reduced Tonic Inhibition In The Basolateral Amygdala During Epileptogenesis, Michael A. Rogawski, Brita Fritsch, Felicia Qashu, T. H. Figueiredo, Vicki Aroniadou-Anderjaska, Maria F.M. Braga
Michael A. Rogawski
An acute brain insult such as traumatic head/brain injury, stroke, or an episode of status epilepticus can trigger epileptogenesis, which, after a latent, seizure-free period, leads to epilepsy. The discovery of effective pharmacological interventions that can prevent the development of epilepsy requires knowledge of the alterations that occur during epileptogenesis in brain regions that play a central role in the induction and expression of epilepsy. In the present study, we investigated pathological alterations in GABAergic interneurons in the rat basolateral amygdala (BLA), and the functional impact of these alterations on inhibitory synaptic transmission, on days 7 to 10 after status …
The Anticonvulsant Activity Of Acetone, The Major Ketone Body In The Ketogenic Diet, Is Not Dependent On Its Metabolites Acetol, 1,2-Propanediol, Methylglyoxal, Or Pyruvic Acid, Maciej Gasior, Amy French, Michelle Joy, Rebecca Tang, Adam Hartman, Michael Rogawski
The Anticonvulsant Activity Of Acetone, The Major Ketone Body In The Ketogenic Diet, Is Not Dependent On Its Metabolites Acetol, 1,2-Propanediol, Methylglyoxal, Or Pyruvic Acid, Maciej Gasior, Amy French, Michelle Joy, Rebecca Tang, Adam Hartman, Michael Rogawski
Michael A. Rogawski
BACKGROUND: Acetone, one of the principal ketone bodies elevated during treatment with the ketogenic diet, exhibits anticonvulsant properties that may contribute to the seizure protection conferred by the diet. The anticonvulsant mechanism of acetone is unknown, but it is metabolized to several bioactive substances that could play a role. METHODS: Acetone and its major metabolites-acetol, 1,2-propanediol, methylglyoxal, and pyruvic acid-were assessed for anticonvulsant activity in two mouse seizure models. Various doses of the substances administered intraperitoneally were characterized for their ability to elevate the threshold for clonic seizures induced by intravenous infusion of pentylenetetrazol (PTZ) and for protection against tonic …
Role Of Ampa And Glur5 Kainate Receptors In The Development And Expression Of Amygdala Kindling In The Mouse, Michael A. Rogawski, Philip S. Kurzman, Shun-Ichi Yamaguchi, He Li
Role Of Ampa And Glur5 Kainate Receptors In The Development And Expression Of Amygdala Kindling In The Mouse, Michael A. Rogawski, Philip S. Kurzman, Shun-Ichi Yamaguchi, He Li
Michael A. Rogawski
The role of AMPA and GluR5-containing kainate receptors in the development and expression of amygdala kindling was examined using the selective 2,3-benzodiazepine AMPA receptor antagonist GYKI 52466 [(1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine] and the decahydroisoquinoline mixed AMPA receptor and GluR5 kainate receptor antagonist LY293558 {(3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline- 3-carboxy lic acid)}. Administration of GYKI 52466 (5-40 mg/kg, intraperitoneally) and LY293558 (10-40 mg/kg, intraperitoneally) prior to daily kindling stimulation in mice produced a dose-dependent suppression of the rate of development of behavioral kindled seizure activity and reduced the duration of the stimulation-induced electrographic afterdischarge. In drug-free stimulation sessions after the initial drug-treatment sessions, there was an …