Medical Pharmacology Commons^™

Characterization Of The Discriminative Stimulus Effects Of Nitrous Oxide, Kellianne J. Richardson

Theses and Dissertations

Nitrous oxide (N2O) is a widely used anesthetic adjunct in dentistry and medicine that is also commonly abused. N2O alters the function of several receptors in vitro and ex vivo, however, the receptors systems underlying its abuse-related intoxicating effects are poorly understood. The goals of this dissertation were to (1) establish N2O as a discriminative stimulus, (2) characterize the temporal properties of the discriminative stimulus, (3) determine the degree of similarity between N2O and other inhalants and (4) explore the neurochemical effects responsible for the stimulus properties of N2O. Twenty-four mice were trained to discriminate 10 minutes exposure to 60% …

Redox Triggering Of Podocyte Nlrp3 Inflammasomes And Glomerular Injury In Hyperhomocysteinemia, Justine M. Abais

Theses and Dissertations

Hyperhomocysteinemia (hHcys), an important pathogenic factor contributing to the progression of end-stage renal disease (ESRD), has been shown to activate NOD-like receptor protein 3 (NLRP3) inflammasomes and cause podocyte dysfunction and glomerular sclerosis. hHcys induces aggregation of the three inflammasome components – NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1 – and its activation is indicated by increased caspase-1 activity and secretion of interleukin-1β (IL-1β). The aims of the present study sought to elucidate the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated redox signaling in hHcys-induced NLRP3 inflammasome activation, to dissect the contribution of common endogenous reactive oxygen species (ROS) …

The Role Of P2x Receptors In Hiv And Opiate-Related Neurotoxicity, Mary Sorrell

Theses and Dissertations

Emerging evidence suggests that opioid drugs can exacerbate neuroAIDS. Microglia are the principal neuroimmune effectors thought to be responsible for neuron damage in HIV-infected individuals, and evidence suggests that drugs acting via opioid receptors in microglia aggravate the neuropathophysiological effects of HIV. The P2X family of ATP activated ligand-gated ion channels regulates key aspects of microglial function. In addition, opioid-dependent microglial activation has been reported to be mediated through P2X4 signaling, prompting us to investigate P2X receptors contribution to the neurotoxic effects of HIV and morphine. In vitro experiments showed treatment with TNP-ATP prevented the neurotoxic effects of morphine and/or …

Bisphenol A Exposure And Cardiac Electrical Conduction In Excised Rat Hearts, Nikki G. Posnack, Rafael Jaimes Iii, Huda Asfour, Luther Swift, Anastasia M. Wengrowski, Narine Sarvazyan, Matthew Kay

Pharmacology and Physiology Faculty Publications

BACKGROUND:

Bisphenol A (BPA) is used to produce polycarbonate plastics and epoxy resins that are widely used in everyday products, such as food and beverage containers, toys and medical devices. Human biomonitoring studies have suggested that a large proportion of the population may be exposed to BPA. Recent epidemiological studies have reported correlations between increased BPA urinary concentrations and cardiovascular disease; yet the direct effects of BPA on the heart are unknown.

OBJECTIVES:

The goal of our studies was to measure BPA's effect (0.1-100 μM) on cardiac impulse propagation ex vivo, using excised whole hearts from adult rats.

METHODS: …

Behavioral Assessment And Hplc/Ms/Ms Identification Of The Synthetic Cannabinoid, Cp47,497, In Mice, Kimberly L. Samano

Theses and Dissertations

CP47,497 and other synthetic cannabinoid compounds were incipiently synthesized as research tools to investigate the mechanisms by which marijuana affects the brain and to aid in the development of therapeutic agents. Recently, these cannabinoid compounds have resurfaced in the designer drug market, marketed as “herbal incense products” (HIPs). Their popular use has resulted in an alarming rate of reported adverse effects and toxicities. Current legislation classified CP47,497 and several other synthetic cannabinoids compounds as Schedule I agents, but abuse of these compounds persists with serious consequences to public health and safety. In vivo studies examining the behavioral consequences of abused …

Ventricular Myocyte Contraction, Calcium Transport And Expression Of Genes Encoding Cardiac Muscle Proteins In Type 2 Diabetic Rats Fed A Sucrose-Enriched Diet, Eslam Mohamed Gaber El Nebrisi

Theses

Diabetes Mellitus (DM) is currently the fastest growing disease in the world. The prevalence of DM has increased worldwide and is expected to double within 20 years. The UAE is ranked 15^th worldwide, with 18.98% of the UAE population living with diabetes. Six Middle East North Africa (MENA) region countries – Bahrain, Egypt, Kuwait, Oman, Saudi Arabia, and United Arab Emirates (UAE) - are among the world’s 10 highest for prevalence of diabetes and impaired glucose tolerance. This represents a huge cost to society in terms of morbidity and mortality, and economically through lost productivity and cost burden on …

Spatiotemporal Expression Of Manf In The Developing Rat Brain, Haiping Wang, Zunji Ke, Alexander Alimov, Mei Xu, Jacqueline A. Frank, Shengyun Fang, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved neurotrophic factor which exhibited neuroprotective properties. Recent studies suggested that MANF may play a role in the neural development of Drosophila and zebra fishes. In this study, we investigated the spatiotemporal expression of MANF in the brain of postnatal and adult rats. MANF expression appeared wide spread and mainly localized in neurons. In the cerebral cortex, neurons in layer IV and VI displayed particularly strong MANF immunoreactivity. In the hippocampus, intensive MANF expression was observed throughout the subfields of Cornu Amonis (CA1, CA2, and CA3) and the granular layer of the …

Aged Rats Are Hypo-Responsive To Acute Restraint: Implications For Psychosocial Stress In Aging, Heather M. Buechel, Jelena Popovic, Kendra Staggs, Katie L. Anderson, Olivier Thibault, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.g., loss of job, death of spouse, social isolation), and aged humans are well-understood to be more vulnerable to the negative consequences of such new-onset chronic psychosocial stress events. However, the mechanistic underpinnings of this age-related shift …

Intracellular Calcium Stores Drive Slow Non-Ribbon Vesicle Release From Rod Photoreceptors, Minghui Chen, David Križaj, Wallace B. Thoreson

Journal Articles: Pharmacology & Experimental Neuroscience

Rods are capable of greater slow release than cones contributing to overall slower release kinetics. Slow release in rods involves Ca(2+)-induced Ca(2+) release (CICR). By impairing release from ribbons, we found that unlike cones where release occurs entirely at ribbon-style active zones, slow release from rods occurs mostly at ectopic, non-ribbon sites. To investigate the role of CICR in ribbon and non-ribbon release from rods, we used total internal reflection fluorescence microscopy as a tool for visualizing terminals of isolated rods loaded with fluorescent Ca(2+) indicator dyes and synaptic vesicles loaded with dextran-conjugated pH-sensitive rhodamine. We found that rather than …

A Direct And Indirect Mechanism For Ccr5 In Morphine And Hiv-1 Mediated Neurodegeneration, Elizabeth Podhaizer

Theses and Dissertations

A DIRECT AND INDIRECT MECHANISM FOR CCR5 IN OPIOID AND HIV-1 MEDIATED NEURODEGENERATION By Elizabeth M. Podhaizer, Ph.D. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2014 Major Director: Kurt F. Hauser, Ph.D., Professor of Pharmacology & Toxicology Human immunodeficiency virus (HIV)-1 infection currently affects over 34 million people worldwide, and despite the use of cART, the prevalence of HIV-1 associated neurocognitive impairments (HAND) has not declined. Additionally, other co-morbid factors such as the abuse of injection drugs (i.e. heroin, morphine) increase both the frequency …

The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates …

Targeting The Endocannabinoid Metabolic Enzymes To Reduce Inflammatory Pain, Sudeshna Ghosh

Theses and Dissertations

Pain is a debilitating condition that presents a problem of clinical relevance. Common analgesics include opioids and non-steroidal anti-inflammatory drugs (NSIADs). Despite different degrees of effectiveness, a major drawback of these analgesic classes is their side effects. For example, side effects associated with opioids include pruritus, respiratory depression, hyperalgesia, constipation, dependence. In addition, chronic use of NSAIDs can cause gastric ulcers. Delta-9 tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, produces antinociception in various preclinical models of pain. Similarly, many synthetic cannabinoid receptor agonists produce antinociception in preclinical models of pain. However, their psychomimetic effects dampen interest for their therapeutic …

Combined Antiproliferative Effects Of The Aminoalkylindole Win55,212-2 And Radiation In Breast Cancer Cells, Sean Emery

Theses and Dissertations

The potential antitumor activity of mixed CB1/CB2 cannabinoid receptor agonists, such as the aminoalkylindole WIN55,212-2 (WIN2), has been extensively studied, but little information is available as to their potential interaction with conventional cancer therapies, such as ionizing radiation (IR). In the present work, we investigated the effects of WIN2 on the antiproliferative effects of radiation in human (MCF-7 and MDA-MB-231) and murine (4T1) breast cancer cells, as well as an immortalized human breast epithelial cell line (MCF-10A). WIN2 or radiation alone inhibited breast tumor growth, while the combination of WIN2 and radiation was more effective than either agent alone in …

The Evolutionary Young Mir-1290 Favors Mitotic Exit And Differentiation Of Human Neural Progenitors Through Altering The Cell Cycle Proteins., Sowmya V. Yelamanchili, Brenda M. Morsey, Emily B. Harrison, D. A. Rennard, Kathleen M. Emanuel, I Thapa, D. R. Bastola, H. S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Regulation of cellular proliferation and differentiation during brain development results from processes requiring several regulatory networks to function in synchrony. MicroRNAs are part of this regulatory system. Although many microRNAs are evolutionarily conserved, recent evolution of such regulatory molecules can enable the acquisition of new means of attaining specialized functions. Here we identify and report the novel expression and functions of a human and higher primate-specific microRNA, miR-1290, in neurons. Using human fetal-derived neural progenitors, SH-SY5Y neuroblastoma cell line and H9-ESC-derived neural progenitors (H9-NPC), we found miR-1290 to be upregulated during neuronal differentiation, using microarray, northern blotting and qRT-PCR. We …

Specific Localization Of Β-Arrestin2 In Myenteric Plexus Of Mouse Gastrointestinal Tract, Hercules T. Maguma, Dipanjana D. De, Sukhada Bhave, William L. Dewey, Hamid I. Akbarali

Pharmacology and Toxicology Publications

Abstract

β-arrestin2 is a key molecule involved in signaling and internalization of activated G protein-coupled receptors including µ-opioid receptors (MOR). Previously we have shown that decreased expression of β-arrestin2 upon chronic morphine is associated with the development of opioid tolerance in the gastrointestinal tract. However, the localization of β-arrestin2 within the gastrointestinal wall is not known. In this study we found that β-arrestin2 is localized in the soma of a select group of neurons in the myenteric ganglia but not in smooth muscle. The density of β-arestin2 was significantly higher in the ileum than the colon. We identified four variants …

Activation Of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition And Migration: Implication Of A Novel Role Of Inflammasome In Atherogenesis, Xiang Li, Yang Zhang, Min Xia, Erich Gulbins, Krishna M. Boini, Pin-Lan Li

Pharmacology and Toxicology Publications

Although Nlrp3 inflammasome activation in macrophages has been shown to be critical for the development of atherosclerosis upon atherogenic stimuli, it remains unknown whether activated Nlrp3 inflammasomes by other non-atherogenic stimuli induce alterations in macrophages that may contribute in the concert with other factors to atherogenesis. Thus, the present study tested the hypothesis that activation of Nlrp3 inflammasomes by ATP, which is a classical non-lipid danger stimulus, enhances the migration of macrophage and increases lipids deposition in macrophages accelerating foam cell formation. We first demonstrated that extracellular ATP (2.5 mM) markedly increased the formation and activation of Nlrp3 inflammasomes in …

Therapeutic Efficacy Of Cerium Oxide Nanoparticles Against Sepsis Induced Multi-Organ Dysfunction Syndrome In Sprague Dawley Rats, Nandini Durga Prasanna Kumar Manne

Theses, Dissertations and Capstones

Sepsis is a generalized term that signifies the presence of a pathogen in the blood stream to which the body responds by eliciting a systemic inflammatory response. Although sepsis is the leading cause of death in non-coronary intensive care units in United States, there are currently no FDA approved therapeutic drugs to treat this disorder. Cerium oxide nanoparticles (CeO₂) have been shown to exhibit anti-oxidant, anti-inflammatory, and anti-bacterial properties both in vitro and in vivo. Whether CeO₂ nanoparticles can be used for the treatment of sepsis is currently unclear.

To investigate whether CeO₂ nanoparticles can …

Concordant Integrative Gene Set Enrichment Analysis Of Multiple Large-Scale Two-Sample Expression Data Sets, Yinglei Lai, Fanni Zhang, Tapan K. Nayak, Reza Modarres, Norman H. Lee, Timothy A. Mccaffrey

Pharmacology and Physiology Faculty Publications

Background

Gene set enrichment analysis (GSEA) is an important approach to the analysis of coordinate expression changes at a pathway level. Although many statistical and computational methods have been proposed for GSEA, the issue of a concordant integrative GSEA of multiple expression data sets has not been well addressed. Among different related data sets collected for the same or similar study purposes, it is important to identify pathways or gene sets with concordant enrichment.

Methods

We categorize the underlying true states of differential expression into three representative categories: no change, positive change and negative change. Due to data noise, what …

Heat Shock Factor 2 Is A Stress‐Responsive Mediator Of Neuronal Migration Defects In Models Of Fetal Alcohol Syndrome, Rachid El Fatimy, Federico Miozzo, Anne Le Mouël, Ryma Abane, Leslie Schwendimann, Délara Sabéran‐Djoneidi, Aurélie De Thonel, Illiasse Massaoudi, Liliana Paslaru, Kazue Hashimoto-Torii, Elisabeth Christians, Pasko Rakic, Pierre Gressens, Valérie Mezger

Pharmacology and Physiology Faculty Publications

Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal andHsf2‐deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post‐translational modifications, and HSF2 steers the formation of atypical alcohol‐specific HSF1–HSF2 heterocomplexes. This perturbs the in vivo binding …

Nudging The Fda, W. Nicholson Price Ii, I. Glenn Cohen

Law Faculty Scholarship

[Excerpt] "The FDA’s regulation of drugs is frequently the subject of policy debate, with arguments falling into two camps. On the one hand, a libertarian view of patients and the health care system holds high the value of consumer choice. Patients should get all the information and the drugs they want; the FDA should do what it can to enforce some basic standards but should otherwise get out of the way. On the other hand, a paternalist view values the FDA’s role as an expert agency standing between patients and a set of potentially dangerous drugs and potentially unscrupulous or …