Medical Sciences Commons^™

Ab Deposition In Idiopathic And Dup15q11.2-Q13 Autism Spectrum Disorders, J Wegiel, Janusz Frackowiak, Bozena Mazur-Kolecka, N Carolyn Schanen, Edwin H. Cook Jr, Marian Sigman, Ted Brown, Izabela Kuchna, Jarek Wegiel, Krzysztof Nowicki, Humi Imaki, Shuang Yong Ma, Abha Chauhan, Ved Chauhan, David L. Miller, Pankaj D. Mehta, Michael Flory, Ira L. Cohen, Eric London, Barry Reisberg, Mony J. De Leon, Thomas Wisnieski

N C Schanen

Background: It has been shown that amyloid ß (Ab), a product of proteolytic cleavage of the amyloid b precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.

Methodology/Principal Findings: In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Ab load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 …

The Faculty For Undergraduate Neuroscience: Learning Lessons Since 1991, Eric P. Wiertelak, Julio J. Ramirez, Jennifer R. Yates

Eric Wiertelak

No abstract provided.

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 …

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 …

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

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

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 …

Laser Capture Sampling And Analytical Issues In Proteomics, Howard Gutstein, Jeffrey S. Morris

Jeffrey S. Morris

Proteomics holds the promise of evaluating global changes in protein expression and post-translational modificaiton in response to environmental stimuli. However, difficulties in achieving cellular anatomic resolution and extracting specific types of proteins from cells have limited the efficacy of these techniques. Laser capture microdissection has provided a solution to the problem of anatomical resolution in tissues. New extraction methodologies have expanded the range of proteins identified in subsequent analyses. This review will examine the application of laser capture microdissection to proteomic tissue sampling, and subsequent extraction of these samples for differential expression analysis. Statistical and other quantitative issues important for …

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 …

Identifying Placebo Effects With Data From Clinical Trials, Anup Malani

Anup Malani

A medical treatment is said to have placebo effects if patients who are optimistic about the treatment respond better to the treatment. This paper proposes a simple test for placebo effects. Instead of comparing the treatment and control arms of a single trial, one should compare the treatment arms of two trials with different probabilities of assignment to treatment. If there are placebo effects, patients in the higher-probability trial will experience better outcomes simply because they believe that there is a greater chance of receiving treatment. This paper finds evidence of placebo effects in trials of antiulcer and cholesterol-lowering drugs.

From Faculty For Undergraduate Neuroscience: Encouraging Innovation In Undergraduate Neuroscience Education By Supporting Student Research And Faculty Development, Eric Wiertelak, J. C. Hardwick, M. Kerchner, B. Lom, J. J. Ramirez

Eric Wiertelak

No abstract provided.

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 …