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Articles 1 - 7 of 7
Full-Text Articles in Medicine and Health Sciences
Current Understanding Of The Mechanism Of Action Of The Antiepileptic Drug Lacosamide, Michael A. Rogawski, Azita Tofighy, H Steve White, Alain Matagne, Christian Wolff
Current Understanding Of The Mechanism Of Action Of The Antiepileptic Drug Lacosamide, Michael A. Rogawski, Azita Tofighy, H Steve White, Alain Matagne, Christian Wolff
Michael A. Rogawski
The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates …
Perampanel Inhibition Of Ampa Receptor Currents In Cultured Hippocampal Neurons, Chao-Yin Chen, Lucas Matt, Johannes Hell, Michael Rogawski
Perampanel Inhibition Of Ampa Receptor Currents In Cultured Hippocampal Neurons, Chao-Yin Chen, Lucas Matt, Johannes Hell, Michael Rogawski
Michael A. Rogawski
Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (τ~1 s at 3 µM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate. The rates of block and unblock of AMPA receptor currents were 1.5×105 M−1 s−1 and 0.58 s−1, respectively. Perampanel did not affect NMDA receptor currents. The extent …
The Potential Of Antiseizure Drugs And Agents That Act On Novel Molecular Targets As Antiepileptogenic Treatments, Rafal M. Kaminski, Michael A. Rogawski, Henrik Klitgaard
The Potential Of Antiseizure Drugs And Agents That Act On Novel Molecular Targets As Antiepileptogenic Treatments, Rafal M. Kaminski, Michael A. Rogawski, Henrik Klitgaard
Michael A. Rogawski
A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferator-activated receptors γ pathways; effects on factors related to thrombolysis, …
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 …
Epilepsy Therapy Development: Technical And Methodologic Issues In Studies With Animal Models, Aristea S. Galanopoulou, Merab Kokaia, Jeffrey A. Loeb, Astrid Nehlig, Asla Pitkanen, Michael A. Rogawski, Kevin J. Staley, Vicky H. Whittemore, F. Edward Dudek
Epilepsy Therapy Development: Technical And Methodologic Issues In Studies With Animal Models, Aristea S. Galanopoulou, Merab Kokaia, Jeffrey A. Loeb, Astrid Nehlig, Asla Pitkanen, Michael A. Rogawski, Kevin J. Staley, Vicky H. Whittemore, F. Edward Dudek
Michael A. Rogawski
The search for new treatments for seizures, epilepsies, and their comorbidities faces considerable challenges. This is due in part to gaps in our understanding of the etiology and pathophysiology of most forms of epilepsy. An additional challenge is the difficulty in predicting the efficacy, tolerability, and impact of potential new treatments on epilepsies and comorbidities in humans, using the available resources. Herein we provide a summary of the discussions and proposals of the Working Group 2 as presented in the Joint American Epilepsy Society and International League Against Epilepsy Translational Workshop in London (September 2012). We propose methodologic and reporting …
Neuroactive Steroids For The Treatment Of Status Epilepticus, Michael Rogawski, Carlos Loya, Kiran Reddy, Dorota Zolkowski, Christoph Lossin
Neuroactive Steroids For The Treatment Of Status Epilepticus, Michael Rogawski, Carlos Loya, Kiran Reddy, Dorota Zolkowski, Christoph Lossin
Michael A. Rogawski
Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABA-A receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzodiazepine resistance, which is believed to be a major cause of treatment failure. GABA-A receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABA-A receptors, but in addition they enhance extrasynaptic GABA-A receptors that mediate tonic inhibition. Extrasynaptic GABA-A receptors are not internalized, and desensitization of these …
Epilepsy, Michael Rogawski