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Full-Text Articles in Medical Neurobiology
Axon Initial Segment Morphology Across Typical Cortical Development And In Mouse Models Of Neurodevelopmental Disorders With A High Incidence Of Epilepsy, Rachel Ali Rodriguez
Axon Initial Segment Morphology Across Typical Cortical Development And In Mouse Models Of Neurodevelopmental Disorders With A High Incidence Of Epilepsy, Rachel Ali Rodriguez
UNLV Theses, Dissertations, Professional Papers, and Capstones
Neurodevelopmental disorders (NDDs) are commonly associated with a high incidence of epileptic seizures which result from excessive firing of neurons. The axon initial segment (AIS) is a neuronal compartment essential for the control of activity patterns of neurons. The AIS undergoes important modifications during development, but the molecular mechanisms that affect the development, morphology, and protein composition of the AIS are still not well understood. We examined AIS morphology of medial prefrontal cortex (mPFC) pyramidal neurons in wildtype mice across development and in two mouse models of NDDs. Results indicate restructurings at the AIS during typical development, some of which …
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 …
Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Neurosteroids—Endogenous Regulators Of Seizure Susceptibility And Role In The Treatment Of Epilepsy, Doodipala S. Reddy, Michael A. Rogawski
Michael A. Rogawski
Certain steroid hormone metabolites that have activity as modulators of GABA-A receptors but lack conventional hormonal effects—including allopregnanolone and allotetrahydrodeoxycorticosterone—are synthesized within the brain, predominantly in principle (excitatory) neurons, and also in peripheral tissues. At low concentrations, such neurosteroids potentiate GABA-A receptor currents, whereas at higher concentrations they directly activate the receptor; large magnitude effects occur on nonsynaptic delta subunit-containing GABA-A receptors that mediate tonic currents. GABA-A receptor modulatory neurosteroids confer seizure protection in diverse animal models, without tolerance during chronic administration. Endogenous neurosteroids may play a role in catamenial epilepsy, stress-induced changes in seizure susceptibility, temporal lobe epilepsy, and …
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 …
Nontraditional Epilepsy Treatment Approaches, Michael A. Rogawski, Gregory L. Holmes
Nontraditional Epilepsy Treatment Approaches, Michael A. Rogawski, Gregory L. Holmes
Michael A. Rogawski
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.
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 …
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.
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 …
Neurosteroids: Endogenous Modulators Of Seizure Susceptibility, Michael A. Rogawski, Doodipala S. Reddy
Neurosteroids: Endogenous Modulators Of Seizure Susceptibility, Michael A. Rogawski, Doodipala S. Reddy
Michael A. Rogawski
No abstract provided.
Epilepsy (Ionotropic Glutamate Receptors As Therapeutic Targets), Wolfgang Löscher, Michael A. Rogawski
Epilepsy (Ionotropic Glutamate Receptors As Therapeutic Targets), Wolfgang Löscher, Michael A. Rogawski
Michael A. Rogawski
No abstract provided.
Excitatory Amino Acids And Seizures, Michael A. Rogawski
Excitatory Amino Acids And Seizures, Michael A. Rogawski
Michael A. Rogawski
No abstract provided.