Copyright (c) 2009 All rights reserved. http://works.bepress.com/michael_rogawski Recent documents in Michael A. Rogawski en-us Wed, 04 Nov 2009 23:18:56 PST 3600 http://works.bepress.com/michael_rogawski/18 http://works.bepress.com/michael_rogawski/18 Tue, 03 Nov 2009 21:24:44 PST In this autobiography and collection of essays, we learn how Harold Varmus created a life of consequence, enabled by his passions, a competitive streak, a certain quirky social deftness, a sixth sense for navigating political minefields, and a dose of chutzpah. Varmus readily admits that it was prizes (actually the Nobel Prize, although he also won the Lasker and many others) that opened doors for him to the halls of power. While the Nobel provides a public voice, it is the rare laureate who can parlay the media attention into a second career as the successful leader of a public institution and from there on to statesmanship. Michael A. Rogawski Book Reviews http://works.bepress.com/michael_rogawski/17 http://works.bepress.com/michael_rogawski/17 Sat, 11 Jul 2009 10:26:39 PDT 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 enhancement of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from BLA pyramidal cells; and 3) blocked ATPA-induced suppression of evoked IPSCs, which is mediated by presynaptic GluK1 kainate receptors present on BLA interneurons. Topiramate (10 microM) had no effect on the AMPA [(R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid]-induced enhancement of spontaneous activity of BLA neurons. Thus, although topiramate inhibits GluK1 kainate receptor- mediated enhancement of interneuron firing, it promotes evoked GABA release, leading to a net inhibition of circuit excitability. In addition, we found that topiramate (0.3-10 microM) increased the amplitude of evoked, spontaneous, and miniature IPSCs in BLA pyramidal neurons, indicating an enhancement of postsynaptic GABA-A receptor responses. Taken together with our previous findings, we conclude that topiramate protects against hyperexcitability in the BLA by suppressing the GluK1 kainate receptor-mediated excitation of principal neurons by glutamatergic afferents, blocking the suppression of GABA release from interneurons mediated by presynaptic GluK1 kainate receptors and directly enhancing GABA-A receptor-mediated inhibitory currents. Maria F.M. Braga Original Research http://works.bepress.com/michael_rogawski/16 http://works.bepress.com/michael_rogawski/16 Wed, 10 Jun 2009 18:08:52 PDT Purpose: Benzodiazepines such as diazepam may fail to effectively treat status epilepticus because benzodiazepine-sensitive GABA-A receptors are internalized progressively with continued seizure activity. Ionotropic glutamate receptors, including AMPA receptors, are externalized, so that AMPA receptor antagonists, which are broad-spectrum anticonvulsants, could be more effective treatments for satus epilepticus. We assessed the ability of the non-competitive AMPA receptor antagonist GYKI 52466 to protect against kainic acid-induced status epilepticus in mice.Methods: Groups of animals treated with kainic acid received GYKI 52466 (50 mg/kg followed in 15 min by 50 mg/kg) or diazepam (25 mg/kg followed in 20 min by 12.5 mg/kg) beginning at 5 min of continuous seizure activity or 25 min later. The duration of seizure activity was determined by EEG recording from epidural cortical electrodes.Results: Both GYKI 52466 and diazepam rapidly terminated electrographic and behavioral seizures when administered early. However, diazepam-treated animals exhibited more seizure recurrences. With late administration, GYKI 52466 also rapidly terminated seizures and they seldom recurred, whereas diazepam was slow to produce seizure control and recurrences were common. Although both treatments caused sedation, GYKI 52466-treated animals retained neurological responsiveness whereas diazepam-treated animals did not. GYKI 52466 did not affect blood pressure whereas diazepam caused a sustained drop in mean arterial pressure.Discussion: Noncompetitive AMPA receptor antagonists represent a promising approach for early treatment of status epilepticus; they may also be effective at later times when there is refractoriness to benzodiazepines. Brita Fritsch Original Research http://works.bepress.com/michael_rogawski/15 http://works.bepress.com/michael_rogawski/15 Wed, 29 Apr 2009 22:10:42 PDT 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 of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of alpha3-containing GABA-A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA-A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA-A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism. Michael A. Rogawski Reviews http://works.bepress.com/michael_rogawski/14 http://works.bepress.com/michael_rogawski/14 Fri, 03 Apr 2009 07:11:29 PDT Overview of articles published in a special issue of Neurotherapeutics (April 2009) on nontraditional (non-drug) epilepsy treatment approaches. From the Fourth Workshop on New Horizons in the Development of Antiepileptic Drugs: Nontraditional Approaches to Treat Epilepsy, which was held at the Clontarf Castle, Dublin, March 5-7, 2008. Michael A. Rogawski Commentaries and Editorials http://works.bepress.com/michael_rogawski/13 http://works.bepress.com/michael_rogawski/13 Fri, 27 Feb 2009 22:07:09 PST 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 that brief CED infusions of nondiffusible peptides that inhibit the release of excitatory neurotransmitters, including omega-conotoxins and botulinum neurotoxins, can produce long-lasting (weeks to months) seizure protection in the rat amygdala-kindling model. Seizure protection is obtainable without detectable neurological or behavioral side effects. Although conventional diffusible antiepileptic drugs do confer seizure protection when administered locally by CED, the effect is transitory. CED is a potential approach for seizure protection that could represent an alternative to resective surgery in the treatment of focal epilepsies that are resistant to orally-administered anti-epileptic drugs. The prolonged duration of action of nondiffusible toxins would allow seizure protection to be maintained chronically with infrequent reinfusions. Michael A. Rogawski Reviews http://works.bepress.com/michael_rogawski/12 http://works.bepress.com/michael_rogawski/12 Wed, 04 Feb 2009 09:17:36 PST 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 had experienced pilocarpine-induced status epilepticus. In the catamenial epilepsy model, there is a marked reduction in the antiseizure potency of anticonvulsant drugs, including benzodiazepines and valproate, but an increase in the anticonvulsant potency and protective index of neurosteroids such as allopregnanolone and the neurosteroid analog ganaxolone. The enhanced seizure susceptibility and benzodiazepine-resistance following neurosteroid withdrawal may be related to reduced expression and altered kinetics of synaptic GABA-A receptors and increased expression of GABA-A receptor subunits (such as alpha4) that confer benzodiazepine insensitivity. The enhanced potency of neurosteroids may be due to a relative increase following neurosteroid withdrawal in the expression of neurosteroid-sensitive delta-subunit-containing perisynaptic/extrasynaptic GABA-A receptors. Positive allosteric modulatory neurosteroids and synthetic analogs such as ganaxolone may be administered to prevent catamenial seizure exacerbations, which we refer to as "neurosteroid replacement therapy." Doodipala S. Reddy Reviews http://works.bepress.com/michael_rogawski/11 http://works.bepress.com/michael_rogawski/11 Wed, 27 Aug 2008 10:01:45 PDT Michael A. Rogawski Book Chapters http://works.bepress.com/michael_rogawski/10 http://works.bepress.com/michael_rogawski/10 Mon, 04 Aug 2008 18:55:35 PDT 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 selectively affecting pain-specific firing; for example, many AEDs suppress high-frequencyaction potentials by blocking voltage-activated sodium channels in a use-dependent fashion. Alternatively, AEDs may specificallytarget pathological channels; for example, gabapentin is a ligand of α2δvoltage-activated calcium channel subunits that areoverexpressed in sensory neurons after nerve injury. Emerging evidence suggests that effects on signaling pathways that regulateneuronal plasticity and survival may be a factor in the delayed clinical efficacy of AEDs in some neuropsychiatric conditions,including bipolar affective disorder. Michael A. Rogawski Reviews http://works.bepress.com/michael_rogawski/9 http://works.bepress.com/michael_rogawski/9 Mon, 04 Aug 2008 18:50:32 PDT 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 by mutations associated with epilepsy in humans. Michael A. Rogawski Reviews