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Articles 31 - 46 of 46
Full-Text Articles in Medical Neurobiology
Rapamycin Rescues Vascular, Metabolic And Learning Deficits In Apolipoprotein E4 Transgenic Mice With Pre-Symptomatic Alzheimer’S Disease, Ai-Ling Lin, Jordan B. Jahrling, Wei Zhang, Nicholas Derosa, Vikas Bakshi, Peter Romero, Veronica Galvan, Arlan Richardson
Rapamycin Rescues Vascular, Metabolic And Learning Deficits In Apolipoprotein E4 Transgenic Mice With Pre-Symptomatic Alzheimer’S Disease, Ai-Ling Lin, Jordan B. Jahrling, Wei Zhang, Nicholas Derosa, Vikas Bakshi, Peter Romero, Veronica Galvan, Arlan Richardson
Sanders-Brown Center on Aging Faculty Publications
Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood–brain barrier integrity and glucose metabolism, compared …
Effects Of Pde4 Pathway Inhibition In Rat Experimental Stroke, Fan Yang, Rachita K. Sumbria, Dong Xue, Chuanhui Yu, Dan He, Shuo Liu, Annlia Paganini-Hill, Mark J. Fisher
Effects Of Pde4 Pathway Inhibition In Rat Experimental Stroke, Fan Yang, Rachita K. Sumbria, Dong Xue, Chuanhui Yu, Dan He, Shuo Liu, Annlia Paganini-Hill, Mark J. Fisher
Pharmacy Faculty Articles and Research
PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the …
Rapid Quantitative Pharmacodynamic Imaging By A Novel Method: Theory, Simulation Testing And Proof Of Principle, Kevin J. Black, Jonathan M. Koller, Brad D. Miller
Rapid Quantitative Pharmacodynamic Imaging By A Novel Method: Theory, Simulation Testing And Proof Of Principle, Kevin J. Black, Jonathan M. Koller, Brad D. Miller
Kevin J. Black, MD
Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, …
Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge
Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge
Pharmacy Faculty Articles and Research
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, …
Ginkgo Extract Egb761 Confers Neuroprotection By Reduction Of Glutamate Release In Ischemic Brain, Alexander Mdzinarishvili, Rachita K. Sumbria, Dorothee Lang, Jochen Klein
Ginkgo Extract Egb761 Confers Neuroprotection By Reduction Of Glutamate Release In Ischemic Brain, Alexander Mdzinarishvili, Rachita K. Sumbria, Dorothee Lang, Jochen Klein
Pharmacy Faculty Articles and Research
Purpose - Ginkgo extract EGb761 has shown anti-edema and anti-ischemic effects in various experimental models. In the present study, we demonstrate neuroprotective effects of EGb761 in experimental stroke while monitoring brain metabolism by microdialysis. Methods - We have used oxygen-glucose deprivation in brain slices in vitro and middle cerebral artery occlusion (MCAO) in vivo to induce ischemia in mouse brain. We used microdialysis in mouse striatum to monitor extracellular concentrations of glucose and glutamate. Results - In vitro, EGb761 reduced ischemia-induced cell swelling in hippocampal slices by 60%. In vivo, administration of EGb761 (300 mg/kg) reduced cell degeneration and edema …
Neuroprotective Effects Of Bilobalide Are Accompanied By A Reduction Of Ischemia-Induced Glutamate Release In Vivo, Dorothee Lang, Cornelia Kiewert, Alexander Mdzinarishvili, Tina Maria Schwarzkopf, Rachita K. Sumbria, Joachim Hartmann, Jochen Klein
Neuroprotective Effects Of Bilobalide Are Accompanied By A Reduction Of Ischemia-Induced Glutamate Release In Vivo, Dorothee Lang, Cornelia Kiewert, Alexander Mdzinarishvili, Tina Maria Schwarzkopf, Rachita K. Sumbria, Joachim Hartmann, Jochen Klein
Pharmacy Faculty Articles and Research
Neuroprotective properties of bilobalide, a specific constituent of Ginkgo extracts, were tested in a mouse model of stroke. After 24 h of middle cerebral artery occlusion (MCAO), bilobalide reduced infarct areas in the core region (striatum) by 40–50% when given at 10 mg/kg 1 h prior to MCAO. Neuroprotection was also observed at lower doses, or when the drug was given 1 h past stroke induction. Sensorimotor function in mice was improved by bilobalide as shown by corner and chimney tests. When brain metabolism in situ was monitored by microdialysis, MCAO caused a rapid disappearance of extracellular glucose in the …
Unifying The Mathematical Modeling Of In Vivo And In Vitro Microdialysis, Peter M. Bungay, Rachita K. Sumbria, Ulrich Bickel
Unifying The Mathematical Modeling Of In Vivo And In Vitro Microdialysis, Peter M. Bungay, Rachita K. Sumbria, Ulrich Bickel
Pharmacy Faculty Articles and Research
A unifying approach is presented for developing mathematical models of microdialysis that are applicable to both in vitro and in vivo situations. Previous models for cylindrical probes have been limited by accommodating analyte diffusion through the surrounding medium in the radial direction only, i.e., perpendicular to the probe axis, or by incomplete incorporation of diffusion in the axial direction. Both radial and axial diffusion are included in the present work by employing two-dimensional finite element analysis. As in previous models, the nondimensional clearance modulus (Θ) represents the degree to which analyte clearance from the external medium influences diffusion through the …
Antiepileptic Drugs And Migraine, Michael Rogawski
Antiepileptic Drugs And Migraine, Michael Rogawski
Michael A. Rogawski
Prepared for the 16th International Headache Research Seminar, “Innovative Drug Development For Headache Disorders,” March 23–25, 2007, Copenhagen, Denmark.
Brivaracetam: A Rational Drug Discovery Success Story, Michael Rogawski
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 …
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 …
Role Of Medial Prefrontal Cortical Group Ii Metabotropic Glutamate Receptor In The Development Of Cocaine Sensitization, Xiaohu Xie
Theses and Dissertations (ETD)
The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was …
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+ …
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 …
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.
Aldosterone Stimulates K Secretion Across Mammalian Colon Independent Of Na Absorption, Gerhard Rechkemmer, Dan R. Halm
Aldosterone Stimulates K Secretion Across Mammalian Colon Independent Of Na Absorption, Gerhard Rechkemmer, Dan R. Halm
Neuroscience, Cell Biology & Physiology Faculty Publications
K transport across guinea pig (Cavia porcellus) distal colon was measured in vitro using isotopically determined unidirectional fluxes. Aldosterone stimulated electrogenic Na absorption, as measured by amiloride-sensitive short-circuit current (Isc), and reduced net K absorption from +2.5 ± 0.2 µEq/cm2 per hr to +0.8 ± 0.3 µEq/cm2 per hr (mean ± SEM). Amiloride addition to the mucosal solution did not enhance net K absorption, as expected if inhibiting active Na absorption would reduce active K secretion as in the distal nephron. The amiloride-insensitive Isc was -1.0 ± 0.2 µEq/cm2 per hr (mean ± SEM) …