Chemicals and Drugs Commons^™

Identification And Characterization Of Novel, Small Molecule Inhibitors Of Spermine Oxidase, Amelia Bryn Furbish

MUSC Theses and Dissertations

The major intracellular polyamines spermine and spermidine are abundant endogenous compounds that are essential for cellular growth and development. Dysregulation of polyamine metabolism has been implicated as a key mechanism of injury across multiple forms of clinically challenging pathologies. Of the enzymes within the polyamine pathway, the catabolic enzyme spermine oxidase (SMOX) is of particular interest as it is subject to induction in response to infection, neuronal excitotoxicity, ischemia, and oxidative stress. In addition to the loss of radical scavenging capabilities associated with spermine depletion, catabolism of spermine by SMOX results in the production of toxic byproducts, including H_{2 …}

Sex Differences In Mood And Anxiety-Related Outcomes In Response To Adolescent Nicotine Exposure, Tsun Hay Jason Ng

Electronic Thesis and Dissertation Repository

Nicotine dependence is causally linked to increased risk of mood/anxiety disorders in later life. Females are reported to experience a higher prevalence of anxiety/depressive disorders and challenges in smoking cessation therapies, suggesting a potential sex-specific response to nicotine exposure and mood/anxiety disorder risk. However, pre-clinical evidence of sex-specific responses to adolescent nicotine exposure is unclear. Thus, to determine any sex differences in anxiety/depressive-related outcomes, adolescent male and female Sprague Dawley rats received nicotine (0.4 mg/kg; 3x daily) or saline injections for 10 consecutive days, followed by behavioural testing, in-vivo electrophysiology and Western Blot analyses. Our results revealed that adolescent nicotine …

Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis, Blake Mcalpin

Dissertations & Theses (Open Access)

One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test …

Investigating The Mitochondrial Protein Mitoneet In C. Elegans Models Of Aging And Alzheimer's Disease, Jacob Ryan Boos

Graduate Theses, Dissertations, and Problem Reports

Oxidative stress is an imbalance between reactive oxygen species production and elimination, favoring the former. Reactive oxygen species serve as important signaling molecules for physiological homeostasis. However, when produced in excess, these once important signaling molecules become detrimental, disrupting cellular functions, and ultimately leading to cell death. In aging, reactive oxygen species production is increased, accompanied with reductions in oxidative stress resistance, increasing the risk for developing age-related diseases including cardiovascular disease, cancer, stroke, and neurodegenerative diseases. The outer mitochondrial membrane iron-sulfur cluster containing protein mitoNEET (CISD1; gene CISD1) has shown to be a mediator of mitochondrial function and …

Evaluating Anesthetic Protocols For Non-Human Primate Functional Neuroimaging, Megha Verma

Electronic Thesis and Dissertation Repository

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to measure a proxy of neural activity in vivo with high spatial specificity. One subject can be followed for a long period of time to assess changes in functional brain organization. However, fMRI is extremely sensitive to motion. The challenges of training non-human primates to reduce motion in an MRI scanner motivate the study of anesthesia which is commonly used to substitute for this training. In this thesis, I compare three different commonly used anesthetic protocols: isoflurane, propofol-fentanyl in combination, and fentanyl alone, to test which of …

Carnosic Acid Differentially Modulates The Nrf2- Antioxidant Response In Male And Female Mice Following Experimental Traumatic Brain Injury, Jacob A. Dunkerson

Theses and Dissertations--Neuroscience

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Each year, an estimated 2.8 million Americans are diagnosed with a TBI due to falling, motor vehicle collisions, gun violence, and sports related concussions. Although inflicted by a single event, the post-traumatic effects of TBI often develop into a life-long disease. Survivors often experience cognitive decline, memory loss, emotional instability, changes in personality, and physical disabilities. A single TBI, and more-so repetitive TBI's, place an individual at a greater risk of developing chronic neurological disorders, such as dementia or Alzheimer’s disease, earlier in life. …

Measuring The Effects Of Lobinaline-N-Bioxide (419) On Alcohol Consumption, Nicotine Locomotor Sensitization, And Conditioned Place Preference In Mice And Rats, Cocanut M. Suhail

Theses and Dissertations--Medical Sciences

Objective: Novel drug 419 was examined to see the effect it has in vivo mice and rats on alcohol consumption, nicotine locomotor sensitization, and conditioned place preference (CPP) models regarding behavioral tests on dopamine transporter activity.

Methods: Mice and rats were used to see how they react to the drug 419 and control vehicle, in each of the models. The animals were assessed to pre- and post- drug administration of novel drug 419. We examined each model to see the association between how drug 419 will help with treating drug abuse.

Results: We found that in alcohol consumption model the …

Investigating The Effects Of Excitotoxic Stimuli On The Suprachiasmatic Nucleus, Rachel A. Brandes

Chancellor’s Honors Program Projects

No abstract provided.

Development And Preclinical Evaluation Of Long-Lasting Cocaine Hydrolases For Cocaine Overdose And Cocaine Use Disorder Treatment, Ting Zhang

Theses and Dissertations--Pharmacy

Cocaine is a plant-based illicit drug commonly involved in substance use disorder. Although cocaine overdose and cocaine use disorders cause adverse health consequences to individuals and the economic burden on their family and society, there are no FDA (Food and Drug Administration) approved medications for treatment. Recently, it has been recognized that delivery of cocaine hydrolase (CocH) is a promising therapeutic strategy. Human butyrylcholinesterase (hBChE), the primary enzyme involved in cocaine metabolism in human, have advantages over other candidates for the development of CocH. Previous studies in our laboratory have designed and characterized hBChE mutants that have ~4,000-fold improved catalytic …

Gene Regulation In The Hypothalamic-Pituitary-Gonadal Axis Of The Green Anole Lizard (Anolis Carolinensis)., Joshua N. Peters

All Graduate Theses, Dissertations, and Other Capstone Projects

Studies examining the hypothalamic-pituitary-gonad axis (HPG) in Anolis carolinensis provide insight into the regulation of this axis under extremely different reproductive conditions. Molecular studies indicate that kisspeptin proteins, transcribed from kiss1 and kiss2 genes, are produced in the hypothalamus where they bind G protein-coupled receptor 54 (GPR54), activating the HPG axis. Gonadotropin inhibitory hormone (GnIH) and its receptors, G protein-coupled receptor 147 and 74 (GPR147 and GPR74), down regulate HPG axis function. In this experiment we examined HPG axis gene expression in the green anole lizard (Anolis carolinensis), a seasonally breeding species with higher steroid hormone levels in the breeding …

Novel Therapeutic Approaches For Juvenile Neuronal Ceroid Lipofuscinosis (Cln3), Megan Elizabeth Bosch

Theses & Dissertations

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in CLN3. Neuronal loss is thought to occur via glutamate excitotoxicity; however, little is known about neuron-astrocyte glutamate regulation in JNCL. We discovered that Cln3^Δex7/8 astrocytes have significantly lower basal spontaneous Ca²⁺ oscillations and decreased responses to glutamate, indicating a disrupted signaling network. Cln3^Δex7/8 astrocytes also displayed significantly lower basal mitochondrial respiration and ATP production, suggesting impaired metabolic functions. Concurrent with diminished astrocyte metabolism and Ca²⁺ signaling, Cln3^Δex7/8 neurons were hyper-responsive to glutamate stimulation. These studies suggest that CLN3 …

Habituation And Dishabituation In The Olfactory Bulb: From Neural Responses To Behavior, Mary Cameron Ogg

Theses and Dissertations (ETD)

Habituation and dishabituation modulate the neural resources and behavioral significance allocated to incoming stimuli across the sensory systems. The purpose of the research presented in this dissertation was to characterize these processes in the mouse olfactory bulb (OB) and to determine if OB acetylcholine (ACh) has a role in physiological and behavioral olfactory dishabituation. Calcium imaging was used to determine the timecourse and magnitude of habituation in different parts of the OB during and after a prolonged odor presentation. Widefield imaging of the dendritic, or glomerular, response of OB output cells demonstrated that prolonged odor input habituates glomerular responses during …

Localization Of Fam171b Mrna Expression In Mouse Brain Using In-Situ Hybridization, Ashani Kumudika Sudasinghe

All Graduate Theses, Dissertations, and Other Capstone Projects

Proteins containing polyglutamine (polyQ) tracts within their primary amino acid sequence are particularly interesting because expansion mutation within them has been shown to underlie a growing list of severe neurodegenerative disorders including Huntington's Disease and several types of Spinocerebellar Ataxias. FAM171B is a novel polyQ protein that was originally identified via large scale sequencing efforts. However, to date, very little is known regarding its normal cellular function and expression pattern. In this study, in situ hybridization was utilized to assess whether FAM171B is expressed in developing (postnatal days 7, 21, 42) and adult mouse brains. The results of the experiments …

Antibodies To Heterogenous Nuclear Ribonucleoprotein A1 Penetrate Neurons Leading To Multiple Downstream Effects Resulting In Neurodegeneration, Joshua Nathan Douglas

Theses and Dissertations (ETD)

Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system. MS is believed to occur in genetically susceptible individuals due to an unknown environmental stimulus. MS patients produce autoantibodies to heterogenous nuclear ribonuclearprotein A1 (hnRNP A1), an RNA binding protein (RBP) highly expressed in neurons. hnRNP A1 functions in pre-mRNA splicing, mRNA trafficking, and translation. Furthermore, the anti-hnRNP A1 antibodies are specific to a N-terminal region termed ‘M9’ which serves as a nuclear export sequence/nuclear localization sequence (NES/NLS) responsible for nuclear/cytoplasmic transport of the protein. In this manuscript we will provide data revealing that anti-hnRNP A1 …

An In Vivo Study Of The Effects Of Perinatal Caffeine Exposure On Synaptic Efficacy In The Hippocampus Of Freely Moving Adult Rats, Jee Eun Park

Senior Theses and Projects

The synapse from the perforant path to the dentate gyrus has been widely used successfully to demonstrate long-term potentiation, a cellular model underlying learning and memory. Caffeine is one of the most widely consumed psychoactive stimulants in the world. Caffeine consumption increases in alertness, improvements in motor skills, and neurological functions, and these effects have promoted its use throughout history. Although the many short term cognitive benefits of caffeine intake are well understood, the long term effects of caffeine exposure have been widely disputed. Despite this, it is estimated that over 80% of women continue to consume caffeine throughout pregnancy. …

How The Manipulation Of The Ras Homolog Enriched In Striatum Alters The Behavioral And Molecular Progression Of Huntington’S Disease, Franklin A. Lee

University of New Orleans Theses and Dissertations

Huntington’s disease is an incurable, progressive neurological disorder characterized by loss of motor control, psychiatric dysfunction, and eventual dystonia leading to death. Despite the fact that this disorder is caused by a mutation in one single gene, there is no cure. The mutant Huntingtin (mHtt) protein is expressed ubiquitously throughout the brain but frank cell death is limited to the striatum. Recent work has suggested that Rhes, Ras homolog enriched in striatum, which is selectively expressed in the striatum, may play a role in Huntington’s disease neuropathology. In vitro studies have shown Rhes to be an E3 ligase for the …

Full-Gestational Exposure To Nicotine And Ethanol Results In Long-Term Dysregulation In The Ventral Tegmental Area, Emily Elizabeth Roguski

Theses and Dissertations (ETD)

Nicotine is considered a gateway drug for other drugs of abuse. The majority of smokers that begin smoking in adolescence, continue into adulthood. Multiple factors have been linked with smoking initiation, including maternal smoking. Drug exposure during pregnancy has long been suspected to exert deleterious effects on the fetal brain. Concurrent use of smoking and drinking alcohol throughout pregnancy is an all too frequent occurrence in the human population especially in disadvantaged and younger women.

The present study investigated the potential contributing factors for the enhanced nicotine selfadministration as seen in offspring with gestational exposure to nicotine and ethanol (Nic+EtOH).* …

Effects Of Intranasally Administered Dnsp-11 On The Central Dopamine System Of Normal And Parkinsonian Fischer 344 Rats, James H. Sonne

Theses and Dissertations--Neuroscience

Due to the blood-brain barrier, delivery of many drugs to the brain has required intracranial surgery which is prone to complication. Here we show that Dopamine Neuron Stimulating Peptide 11 (DNSP-11), following non-invasive intranasal administration, protects dopaminergic neurons from a lesion model of Parkinson’s disease in the rat. A significant and dose-dependent increase in an index of dopamine turnover (the ratio of DOPAC to dopamine) was observed in the striatum of normal young adult Fischer 344 rats by whole-tissue neurochemistry compared to vehicle administered controls.

Among animals challenged with a moderate, unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the substantia nigra, those …

The Mesocorticolimbic Dopamine Pathway Reconstituted In Vitro: Glutamate Receptors And Corticosteroid-Methamphetamine Neurotoxicity, Jennifer N. Berry

Theses and Dissertations--Psychology

Stress promotes the use of methamphetamine and other recreational substances and is often implicated in relapse to stimulant use. Thus, it is of critical importance to examine the consequences of the co-occurance of stress and methamphetamine use. Activity of the glutamatergic N-methyl D-aspartate (NMDA) receptor system appears to be involved in the neurotoxic effects of both chronic stress and methamphetamine exposure. The current studies investigated the hypothesis that chronic pre-exposure to the stress hormone corticosterone (CORT) results in an increase of NMDA receptor activity and that this will potentiate the neurotoxic effects of methamphetamine (METH). Co-cultures of the …

Is Chronic Use Of Bacopa Monnieri An Effective Treatment To Improve Memory Performance In Healthy And Aging Adults?, Brian M. Kairalla

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of the systematic review is to determine whether or not chronic use of Bacopa monnieri is an effective treatment to improve memory performance in healthy and aging adults.

Developmental Expression Of Rat Target Of The Antiproliferative Antibody (Rtapa) Protein In The Brain, Clyde Dale Sullivan

Theses and Dissertations (ETD)

The present study defines the expression pattern of rTAPA (CD81) in the developing rat brain. rTAPA is a member of the tetramembrane spanning family of proteins, and like other members of this family, appears to be associated with the stabilization of cellular contacts. On immunoblots of the brain, rTAPA is present in higher levels than any other tissue examined: muscle, tendon, peripheral nerve, cartilage, liver, kidney, skin, and testicle. Immunohistochemical methods were used to define the distribution of rTAPA in the brain. This protein is expressed by ependyma, choroid plexus, astrocytes, and oligodendrocytes, and rTAPA is dramatically upregulated at the …