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Full-Text Articles in Medical Neurobiology
Preclinical Pharmacology Of Perampanel, A Selective Non-Competitive Ampa Receptor Antagonist, Michael A. Rogawski, Takahisa Hanada
Preclinical Pharmacology Of Perampanel, A Selective Non-Competitive Ampa Receptor Antagonist, Michael A. Rogawski, Takahisa Hanada
Michael A. Rogawski
Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile; E2007] is a potent, selective, orally active non-competitive AMPA receptor antagonist developed for the treatment of epilepsy. Perampanel has a 2,3′-bipyridin-6′-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes. Studies in various physiological systems indicate that perampanel selectively inhibits AMPA receptor-mediated synaptic excitation without affecting NMDA receptor responses. Blocking of AMPA receptors occurs at an allosteric site that is distinct from the glutamate recognition site. Radioligand-binding studies suggest that the blocking site coincides with that of the non-competitive antagonist GYKI 52466, believed to be on linker peptide segments of AMPA receptor subunits that transduce …
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.
Revisiting Ampa Receptors As An Antiepileptic Drug Target, Michael A. Rogawski
Revisiting Ampa Receptors As An Antiepileptic Drug Target, Michael A. Rogawski
Michael A. Rogawski
In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As …
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 …
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 …
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 …
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 …
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.
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+ …
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 …
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 …
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.