Medical Sciences Commons^™

Exploring The Efficacy Of Mir-33 Antagonism In Promoting Regression Of Intracranial Atherosclerosis In A Nonhuman Primate Model, Peter Hecker

Theses and Dissertations--Pharmacology and Nutritional Sciences

Atherosclerosis, characterized by lipid accumulation and arterial inflammation, is a major contributor to global morbidity and mortality. Despite significant progress in understanding atherosclerosis in extracranial arteries, the study of intracranial atherosclerosis (ICAS) has been relatively neglected, despite its crucial role in stroke and vascular cognitive impairment. Challenges related to ICAS, including its location within the cranium and limited availability of suitable animal models, have hindered research progress in this area. Although nonhuman primates (NHPs) are commonly used for studying extracranial atherosclerosis, a comprehensive understanding of ICAS pathophysiology in these animals is lacking. By subjecting NHPs to a high-fat/cholesterol diet, we …

Mitochondria As Causes Of And Therapeutic Targets In Chronic Post-Sepsis Skeletal Muscle Weakness, Meagan Scott Kingren

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis, or the organ damage that ensues after the body fails to properly contain a local infection, is the leading cause of in-patient hospitalization in the United States. Advances in critical care medicine over the last 20 years have enabled most sepsis patients to survive the life-threatening dysregulated immune response. However, a majority of survivors report chronic weakness and fatigue years after sepsis, and the cause of this weakness remains largely unknown. This dissertation work focused first on elucidating the major causes of post-sepsis muscle weakness (Aim 1). This aim involved a time-course study to determine when muscle weakness was …

Neuroprotective Strategies Following Experimental Traumatic Brain Injury: Lipid Peroxidation-Derived Aldehyde Scavenging And Inhibition Of Mitochondrial Permeability Transition, Jacqueline Renee Kulbe

Theses and Dissertations--Neuroscience

Traumatic brain injury (TBI) represents a significant health crisis. To date there are no FDA-approved pharmacotherapies available to prevent the neurologic deficits caused by TBI. Following TBI, dysfunctional mitochondria generate reactive oxygen and nitrogen species, initiating lipid peroxidation (LP) and the formation of LP-derived neurotoxic aldehydes, which bind mitochondrial proteins, exacerbating dysfunction and opening of the mitochondrial permeability pore (mPTP), resulting in extrusion of mitochondrial sequestered calcium into the cytosol, and initiating a downstream cascade of calpain activation, spectrin degradation, neurodegeneration and neurologic impairment.

As central mediators of the TBI secondary injury cascade, mitochondria and LP-derived neurotoxic aldehydes make promising …

Muscle Synergy During A Single Leg Standing Test In Ambulatory Children With Cerebral Palsy, Brennan L. Smith

Theses and Dissertations--Kinesiology and Health Promotion

INTRODUCTION: Cerebral Palsy (CP) is a sensorimotor disorder characterized by dysfunctional motor coordination, balance problems, and loss of selective motor control. Motor coordination exhibited as co-contraction, has been subjectively quantified using gait analysis, but recent studies have begun to objectively analyze the amount of co-contraction by collecting electromyography (EMG) data. Center of pressure excursion (COPE) measurements collected during a single leg standing test (SLST) have shown to be more valid measurements of balance in populations with motor disabilities than a SLST alone. A recent study has correlated increased COPE velocity with a lower fall risk as determined by reported fall …

Neuroinflammation In Alzheimer's Disease And Vascular Cognitive Impairment, Erica M. Weekman

Theses and Dissertations--Physiology

It was once believed that the brain was immunologically privileged with no resident or infiltrating immune cells; however, now it is understood that the cells of the brain are capable of a wide range of inflammatory processes and phenotypes. Inflammation in the brain has been implicated in several disease processes such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID); however, the role of inflammation in these two dementias is poorly understood.

When we stimulated a pro-inflammatory phenotype with an adeno-associated viral vector in a transgenic mouse model of AD that develops Aβ plaques, we saw a pro-inflammatory …

Chronic Pancreatitis, Pain, And Anxiety In An Alcohol And High Fat Mouse Model, Tiffanie Clinkinbeard

Theses and Dissertations--Gerontology

Homeodynamic space (HDS) shrinks as vulnerability increases with aging and repeated damage to the cells. HDS is lost in alcoholic pancreatitis patients due to overconsumption of alcohol, smoking, and high fat diets. Etiologically relevant animal models for study of chronic pancreatitis (CP) are needed. In order to begin filling this gap a central purpose of this dissertation research was to examine relationships between the alcohol and high fat diet (AHF) and pancreatitis with attention to hypersensitivity and anxiety-like behaviors. The AHF diet induced pancreatitis described here etiologically mimics human risk factors of AHF consumption for advancement to alcoholic CP.

In …

Looking To The Future Of Stroke Treatment: Combining Recanalization And Neuroprotection In Acute Ischemic Stroke, Michael E. Maniskas

Theses and Dissertations--Neuroscience

Stroke is the 5^th leading cause of death in the U.S. with 130,000 deaths and around 800,000 affected annually. Currently, there is a significant disconnect between basic stroke research and clinical stroke therapeutic needs. Few animal models of stroke target the large vessels that produce cortical deficits seen in the clinical setting. Also, current routes of drug administration, intraperitoneal and intravenous, do not mimic the clinical route of intra-arterial drug administration. To bridge this divide, we have retro-engineered a mouse model of stroke from the current standard of care for emergent large vessel occlusion (ELVO) stroke, endovascular thrombectomy, to …

Sex Differences In Cell Death And Steroid Hormone Receptors In Cortical Explants, Amanda L. Trout

Theses and Dissertations--Physiology

Estrogens, such as the biologically active 17-b estradiol (E2) have many actions in the male and female brain. Not only does E2 regulate reproductive behavior in adults, it organizes and activates the brains of younger animals in a sex-specific manner. In addition, many human studies have shown E2 to provide protection against a variety of neurological disorders, including stoke. These studies have been controversial and depend largely on the type and timing of hormone replacement. Animal studies are much less controversial and clearly demonstrate a neuroprotective role for E2 following ischemic brain injury. Because much of E2 neuroprotection requires sex …

Blast-Induced Brain Injury: Influence Of Shockwave Components, Dexter V. Reneer

Theses and Dissertations--Neuroscience

Blast-induced traumatic brain injury (bTBI) has been described as the defining injury of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF). Previously, most blast injury research has focused on the effects of blast on internal, gas filled organs due to their increased susceptibility. However, due to a change in enemy tactics combined with better armor and front-line medical care, bTBI has become one of the most common injuries due to blast. Though there has been a significant amount of research characterizing the brain injury produced by blast, a sound understanding of the contribution of each component of the shockwave to the …

Nigrostriatal Dopamine-Neuron Function From Neurotrophic-Like Peptide Treatment And Neurotrophic Factor Depletion, Ofelia Meagan Littrell

Theses and Dissertations--Neuroscience

Trophic factors have shown great promise in their potential to treat neurological disease. In particular, glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor for midbrain dopamine (DA) neurons in the substantia nigra (SN), which lose function in Parkinson’s disease (PD). GDNF progressed to phase II clinical trials, which did not meet proposed endpoints. The large size and binding characteristics of GDNF have been suspected to contribute to some of the shortcomings of GDNF related to delivery to target brain regions. Smaller peptides derived from GDNF (Dopamine-Neuron Stimulating Peptides – DNSPs) have been recently investigated …

Role Of Cyclophilin D In Secondary Spinal Cord And Brain Injury, Jordan Mills Clark

University of Kentucky Doctoral Dissertations

In the hours and days following acute CNS injury, a secondary wave of events is initiated that exacerbate spinal tissue damage and neuronal cell death. A potential mechanism driving these secondary events is opening of the mitochondrial permeability transition pore (mPTP) and subsequent release of several cell death proteins. Previous studies have shown that inhibition of cyclophilin D(CypD), the key regulating component in mPTP opening, was protective against insults that induce necrotic cell death. We therefore hypothesized that CypD-null mice would show improved functional and pathological outcomes following spinal cord injury (SCI) and traumatic brain injury (TBI). Moderate and severe …

Glutamate Regulation In The Hippocampal Trisynaptic Pathway In Aging And Status Epilepticus, Michelle Lee Stephens

University of Kentucky Doctoral Dissertations

A positive correlation exists between increasing age and the incidence of hippocampal-associated dysfunction and disease. Normal L-glutamate neurotransmission is absolutely critical for hippocampal function, while abnormal glutamate neurotransmission has been implicated in many neurodegenerative diseases. Previous studies, overwhelmingly utilizing ex vivo methods, have filled the literature with contradicting reports about hippocampal glutamate regulation during aging. For our studies, enzyme-based ceramic microelectrode arrays (MEA) were used for rapid (2 Hz) measurements of extracellular glutamate in the hippocampal trisynaptic pathway of young (3-6 months), late-middle aged (18 mo.) and aged (24 mo.) urethane-anesthetized Fischer 344 rats. Compared to young animals, glutamate terminals …

Role Of Reactive Oxygen Species Peroxynitrite In Traumatic Spinal Cord Injury, Yiqin Xiong

University of Kentucky Doctoral Dissertations

Peroxynitrite (PN, ONOO-), formed by nitric oxide radical (^•NO) and superoxide radical (O2^•-), plays an important role in post-traumatic oxidative damage. In the early work, we determined the temporal characteristics of PN-derived oxidative damage in a rat spinal cord injury (SCI) model. Our results showed 3-nitrotyrosine (3-NT), a specific marker for PN, rapidly accumulated at early time points (1 hr, 3 hrs), after when it plateaued and the high level was sustained to 1 week post injury. The co-localization of 3-NT and lipid peroxidation derived-4-HNE observed in immunohistochemistry indicates PN is involved in lipid peroxidative as …