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Full-Text Articles in Neuroscience and Neurobiology
Issues Related To Development Of New Antiseizure Treatments, Karen S. Wilcox, Tracy Dixon-Salazar, Graeme J. Sills, Elinor Ben-Menachem, H. Steve White, Roger J. Porter, Marc A. Dichter, Solomon L. Moshe, Jeffrey L. Noebels, Michael D. Privitera, Michael A. Rogawski
Issues Related To Development Of New Antiseizure Treatments, Karen S. Wilcox, Tracy Dixon-Salazar, Graeme J. Sills, Elinor Ben-Menachem, H. Steve White, Roger J. Porter, Marc A. Dichter, Solomon L. Moshe, Jeffrey L. Noebels, Michael D. Privitera, Michael A. Rogawski
Michael A. Rogawski
This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address …
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 …
Glia And Epilepsy: Excitability And Inflammation, Orrin Devinsky, Annamaria Vezzani, Souhel Najjar, Nihal C. De Lanerolle, Michael A. Rogawski
Glia And Epilepsy: Excitability And Inflammation, Orrin Devinsky, Annamaria Vezzani, Souhel Najjar, Nihal C. De Lanerolle, Michael A. Rogawski
Michael A. Rogawski
Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by nonneuronal cells, the glia – especially astrocytes and microglia – in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.
Ampa Receptors As A Molecular Target In Epilepsy Therapy, Michael A. Rogawski
Ampa Receptors As A Molecular Target In Epilepsy Therapy, Michael A. Rogawski
Michael A. Rogawski
Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of nonconventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may …
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 …
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 …
Treatment Of Infantile Spasms: Emerging Insights From Clinical And Basic Science Perspectives, Carl Stafstrom, Barry Arnason, Tallie Baram, Anna Catania, Miguel Cortez, Tracy Glauser, Michael Pranzatelli, Raili Riikonen, Michael Rogawski, Shlomo Shinnar, John Swann
Treatment Of Infantile Spasms: Emerging Insights From Clinical And Basic Science Perspectives, Carl Stafstrom, Barry Arnason, Tallie Baram, Anna Catania, Miguel Cortez, Tracy Glauser, Michael Pranzatelli, Raili Riikonen, Michael Rogawski, Shlomo Shinnar, John Swann
Michael A. Rogawski
Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s) of action is unknown. This review describes the emerging candidate mechanisms that can underlie the therapeutic effects of ACTH in infantile spasms. These mechanisms can ultimately help to improve understanding and treatment of the disease. An overview of current treatments …
Neurosteroid Replacement Therapy For Catamenial Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Neurosteroid Replacement Therapy For Catamenial Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Michael A. Rogawski
Perimenstural catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABA-A receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that following neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epleptic rats that …
Convection-Enhanced Delivery In The Treatment Of Epilepsy, Michael A. Rogawski
Convection-Enhanced Delivery In The Treatment Of Epilepsy, Michael A. Rogawski
Michael A. Rogawski
Convection-enhanced delivery (CED) is a novel drug-delivery technique that uses positive hydrostatic pressure to deliver a fluid containing a therapeutic substance by bulk flow directly into the interstitial space within a localized region of the brain parenchyma. CED circumvents the blood-brain barrier and provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches. A potential use of CED is for the local delivery of antiseizure agents, which would provide an epilepsy treatment approach that avoids the systemic toxicities of orally administered anti-epileptic drugs and bystander effects on nonepileptic brain regions. Recent studies have demonstrated …
Intrinsic Severity As A Determinant Of Antiepileptic Drug Refractoriness, Michael A. Rogawski, Michael R. Johnson
Intrinsic Severity As A Determinant Of Antiepileptic Drug Refractoriness, Michael A. Rogawski, Michael R. Johnson
Michael A. Rogawski
For the most part, resistance to medications in epilepsy is independent of the choice of antiepileptic drug. This simple clinical observation constrains the possible biological mechanisms for drug refractory epilepsy by imposing a requirement to explain resistance for a diverse set of chemical structures that act on an even more varied group of molecular targets. To date, research on antiepileptic drug refractoriness has been guided by the “drug transporter overexpression” and the “reduced drug-target sensitivity” hypotheses. These concepts posit that drug refractoriness is a condition separate from the underlying epilepsy. Inadequacies in both hypotheses mandate a fresh approach to the …
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 …
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 …
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 …
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 …
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.