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Articles 1 - 8 of 8
Full-Text Articles in Life Sciences
How Theories Evolved Concerning The Mechanism Of Action Of Barbiturates, Wolfgang Löscher, Michael A. Rogawski
How Theories Evolved Concerning The Mechanism Of Action Of Barbiturates, Wolfgang Löscher, Michael A. Rogawski
Michael A. Rogawski
The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ-aminobutyric acid (GABA) on GABA-A) receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABA-A) receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3 GABA-A)-receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent …
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 …
Migraine And Epilepsy—Shared Mechanisms Within The Family Of Episodic Disorders, Michael A. Rogawski
Migraine And Epilepsy—Shared Mechanisms Within The Family Of Episodic Disorders, Michael A. Rogawski
Michael A. Rogawski
Migraine and epilepsy are episodic disorders that share many clinical features and underlying pathophysiological mechanisms. Cortical spreading depression (CSD), a wave of profound cellular depolarization, is believed to underlie migraine aura and to be a trigger for the headache pain in migraine. However, the initial event preceding CSD is cellular hyperexcitability associated with localized epileptiform discharges. Glutamate is a critical mediator of the hyperexcitability in both focal seizures and migraine. In focal epilepsy, seizure generation and spread is mediated by synaptically released glutamate acting on AMPA receptors, whereas triggering of CSD depends on NMDA receptors and spread does not require …
Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Michael A. Rogawski
Certain steroid hormone metabolites that have activity as modulators of GABA-A receptors but lack conventional hormonal effects—including allopregnanolone and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly in principle (excitatory) neurons, and also in peripheral tissues. At low concentrations, such neurosteroids potentiate GABA-A receptor currents, whereas at higher concentrations they directly activate the receptor; large magnitude effects occur on nonsynaptic delta subunit-containing GABA-A receptors that mediate tonic currents. GABA-A receptor modulatory neurosteroids confer seizure protection in diverse animal models, without tolerance during chronic administration. Endogenous neurosteroids may play a role in catamenial epilepsy, stress-induced changes in seizure susceptibility, temporal lobe epilepsy, and …
Mechanisms Of Action Of Antiseizure Drugs (Chapter 39), Roger J. Porter, Ashish Dhir, Robert L. Macdonald, Michael A. Rogawski
Mechanisms Of Action Of Antiseizure Drugs (Chapter 39), Roger J. Porter, Ashish Dhir, Robert L. Macdonald, Michael A. Rogawski
Michael A. Rogawski
No abstract provided.