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Articles 31 - 53 of 53
Full-Text Articles in Medical Neurobiology
What Clinical Observations On The Epidemiology Of Antiepileptic Drug Intractability Tell Us About The Mechanisms Of Pharmacoresistance, Michael Rogawski
What Clinical Observations On The Epidemiology Of Antiepileptic Drug Intractability Tell Us About The Mechanisms Of Pharmacoresistance, Michael Rogawski
Michael A. Rogawski
In the past several years, there have been important advances in the clinical epidemiology of antiepileptic drug resistance, as reviewed by Mohanraj and Brodie. It would appear that by and large, intractability is independent of the choice of antiepileptic drug (AED). Many patients will become seizure free on the first agent tried, irrespective of which one their physician decides to pick. Nonresponders to the first drug are in a different category: it is likely that they will continue to have seizures no matter which medicine or combination of medicines is tried. This simple clinical observation puts important constraints on the …
Antiepileptic Drugs And Migraine, Michael Rogawski
Antiepileptic Drugs And Migraine, Michael Rogawski
Michael A. Rogawski
Prepared for the 16th International Headache Research Seminar, “Innovative Drug Development For Headache Disorders,” March 23–25, 2007, Copenhagen, Denmark.
Brivaracetam: A Rational Drug Discovery Success Story, Michael Rogawski
Brivaracetam: A Rational Drug Discovery Success Story, Michael Rogawski
Michael A. Rogawski
Levetiracetam, the alpha-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a approximately 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity …
New Molecular Targets For Antiepileptic Drugs: Alpha2delta, Sv2a, And Kv7/Kcnq/M Potassium Channels, Michael A. Rogawski, Carl W. Bazil
New Molecular Targets For Antiepileptic Drugs: Alpha2delta, Sv2a, And Kv7/Kcnq/M Potassium Channels, Michael A. Rogawski, Carl W. Bazil
Michael A. Rogawski
Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on gamma-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: alpha(2)delta, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam …
Cellular Effects Of Antiepileptic Drugs, Robert L. Macdonald, Michael A. Rogawski
Cellular Effects Of Antiepileptic Drugs, Robert L. Macdonald, Michael A. Rogawski
Michael A. Rogawski
Antiepileptic drugs (AEDs) protect against seizures through interactions with a variety of cellular targets, which include various ion channels, a neurotransmitter transporter, a neurotransmitter metabolic enzyme, and a synaptic vesicle protein. AED actions on these targets can be categorized into four broad groups: 1. Modulation of voltage-dependent ion channels (mainly sodium [Na] but also calcium [Ca] channels) 2. Effects on γ-aminobutyric acid (GABA) systems, including alterations in the cellular disposition of GABA and enhancement of synaptic inhibition mediated by GABA-A receptors 3. Inhibition of synaptic excitation mediated by ionotropic glutamate receptors 4. Modulation of neurotransmitter release, particularly of glutamate, through …
Common Pathophysiologic Mechanisms In Migraine And Epilepsy, Michael A. Rogawski
Common Pathophysiologic Mechanisms In Migraine And Epilepsy, Michael A. Rogawski
Michael A. Rogawski
Migraine and epilepsy are comorbid episodic disorders that have common pathophysiologic mechanisms. Migraine attacks, like epileptic seizures, may be triggered by excessive neocortical cellular excitability; in migraine, however, the hyperexcitability is believed to transition to cortical spreading depression rather than to the hypersynchronous activity that characterizes seizures. Some forms of epilepsy and migraine are known to be channelopathies. Mutations in the same genes can cause either migraine or epilepsy or, in some cases, both. Given the likely commonalities in the underlying cellular and molecular mechanisms, it is not surprising that some antiepileptic drugs, including valproate, topiramate, and gabapentin, are effective …
The Neuropharmacology Of The Ketogenic Diet, Adam Hartman, Maciej Gasior, Elaine Vining, Michael Rogawski
The Neuropharmacology Of The Ketogenic Diet, Adam Hartman, Maciej Gasior, Elaine Vining, Michael Rogawski
Michael A. Rogawski
The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone …
Epilepsy: Mechanisms Of Drug Action And Clinical Treatment, William Theodore, Michael Rogawski
Epilepsy: Mechanisms Of Drug Action And Clinical Treatment, William Theodore, Michael Rogawski
Michael A. Rogawski
No abstract provided.
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 …
Molecular Targets For Antiepileptic Drug Development, Brian S. Meldrum, Michael A. Rogawski
Molecular Targets For Antiepileptic Drug Development, Brian S. Meldrum, Michael A. Rogawski
Michael A. Rogawski
This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the alpha subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, alpha2-delta voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ …
Neuroprotective And Disease-Modifying Effects Of The Ketogenic Diet, Maciej Gasior, Michael A. Rogawski, Adam L. Hartman
Neuroprotective And Disease-Modifying Effects Of The Ketogenic Diet, Maciej Gasior, Michael A. Rogawski, Adam L. Hartman
Michael A. Rogawski
The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, and may also be protective in traumatic brain injury and stroke. These observations are supported by studies in animal models and isolated …
Diverse Mechanisms Of Antiepileptic Drugs In The Development Pipeline, Michael A. Rogawski
Diverse Mechanisms Of Antiepileptic Drugs In The Development Pipeline, Michael A. Rogawski
Michael A. Rogawski
There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cell-based studies, often years after the initial identification …
Alcohol Withdrawal Seizures, Michael A. Rogawski, Prosper N'Gouemo
Alcohol Withdrawal Seizures, Michael A. Rogawski, Prosper N'Gouemo
Michael A. Rogawski
No abstract provided.
The Neurobiology Of Antiepileptic Drugs For The Treatment Of Nonepileptic Conditions, Michael A. Rogawski, Wolfgang Löscher
The Neurobiology Of Antiepileptic Drugs For The Treatment Of Nonepileptic Conditions, Michael A. Rogawski, Wolfgang Löscher
Michael A. Rogawski
Antiepileptic drugs (AEDs) are commonly prescribed for nonepileptic conditions, including migraine headache, chronicneuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calciumchannels or by promoting inhibition mediated by γ-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerveinjury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predisposeneurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs maycounteract this abnormal activity by …
The Neurobiology Of Antiepileptic Drugs, Michael Rogawski, Wolfgang Löscher
The Neurobiology Of Antiepileptic Drugs, Michael Rogawski, Wolfgang Löscher
Michael A. Rogawski
Antiepileptic drugs (AEDs) provide satisfactory control of seizures for most patients with epilepsy. The drugs have the remarkable ability to protect against seizures while permitting normal functioning of the nervous system. AEDs act on diverse molecular targets to selectively modify the excitability of neurons so that seizure-related firing is blocked without disturbing non-epileptic activity. This occurs largely through effects on voltage-gated sodium and calcium channels, or by promoting inhibition mediated by GABA-A (γ-aminobutyric acid, type A) receptors. The subtle biophysical modifications inchannel behaviour that are induced by AEDs are often functionally opposite to defects in channel properties that are caused …
Neurosteroids: Endogenous Modulators Of Seizure Susceptibility, Michael A. Rogawski, Doodipala S. Reddy
Neurosteroids: Endogenous Modulators Of Seizure Susceptibility, Michael A. Rogawski, Doodipala S. Reddy
Michael A. Rogawski
No abstract provided.
Principles Of Antiepileptic Drug Action, Michael Rogawski
Principles Of Antiepileptic Drug Action, Michael Rogawski
Michael A. Rogawski
No abstract provided.
Epilepsy (Ionotropic Glutamate Receptors As Therapeutic Targets), Wolfgang Löscher, Michael A. Rogawski
Epilepsy (Ionotropic Glutamate Receptors As Therapeutic Targets), Wolfgang Löscher, Michael A. Rogawski
Michael A. Rogawski
No abstract provided.
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 …
Of Blind Men And Brain Steroids, Michael A. Rogawski
Of Blind Men And Brain Steroids, Michael A. Rogawski
Michael A. Rogawski
Review of "Neurosteroids: A New Regulatory Function in the Nervous System" (edited by Etiene-Emile Baulieu, Paul Robel and Michael Schumacher), Humana Press, 1999. ISBN 0896 03545X The first recognized example of the profound influence of steroid hormones on the nervous system was perhaps the observation in prehistoric times that animal behaviour changes dramatically during oestrus (the period of female sexual receptivity). In recent years, much specific evidence has accumulated confirming that steroids affect the structure and function of the nervous system through effects on neurogenesis, cell death, cell migration, synapse formation and neuronal excitability.
Ampa Receptors In Epilepsy And As Targets For Antiepileptic Drugs, Michael A. Rogawski, Sean D. Donevan
Ampa Receptors In Epilepsy And As Targets For Antiepileptic Drugs, Michael A. Rogawski, Sean D. Donevan
Michael A. Rogawski
No abstract provided.
Excitatory Amino Acids And Seizures, Michael A. Rogawski
Excitatory Amino Acids And Seizures, Michael A. Rogawski
Michael A. Rogawski
No abstract provided.
Antiepileptic Drugs: Pharmacological Mechanisms And Clinical Efficacy With Consideration Of Promising Developmental Stage Compounds, Michael A. Rogawski, Roger J. Porter
Antiepileptic Drugs: Pharmacological Mechanisms And Clinical Efficacy With Consideration Of Promising Developmental Stage Compounds, Michael A. Rogawski, Roger J. Porter
Michael A. Rogawski
No abstract provided.