Physiology Commons^™

Examination Of Sex- And Limb-Specific Fatigue During Unilateral, Isometric Forearm Exercise, Caleb Christian Voskuil

Theses and Dissertations--Kinesiology and Health Promotion

The purpose of this study was to examine the effects of unilateral, isometric handgrip holds to failure for the dominant (Dm) and non-dominant (NDm) limb on ipsilateral ([IPS] exercised side) and contralateral ([CON] non-exercised side) performance fatigability. Twenty individuals participated in this study (Men [n =10]; Women [n = 10; Composite Demographics: Age: 22.2 years; Height: 174.4 cm; Body Mass: 75.0 kg) and completed three visits. Two, 6 s maximal voluntary isometric contractions (MVICs) for the Dm and NDm limb were performed during visit 1, followed by a familiarization of the fatigue test. Visits 2 and 3 included an isometric, …

Quadriceps Recruitment And Twitch Properties In Lean And Obese Women Before And After Fatiguing Exercise, Rebekah Seay Carpenter

Theses and Dissertations--Kinesiology and Health Promotion

Skeletal muscle strength, specifically that of the anti-gravitational muscles such as the quadriceps, is essential for performing dynamic tasks including walking, navigating stairs, and transitioning between sitting and standing. Obesity has been shown to negatively impact musculoskeletal function and decrease quadriceps strength relative to body weight. Additionally, obesity has been linked with higher rates of fatigue and lower strength outcomes following a test of muscular endurance of the quadriceps. Since obesity lowers relative strength, it is likely that quadriceps muscle weakness contributes to reduced physical function of dynamic tasks. However, to date, the precise mechanism for obesity-induced muscle weakness has …

Novel Mammalian Models For Understanding And Treating Spinal Cord Injury, Michael B. Orr

Theses and Dissertations--Physiology

Spinal cord injury (SCI) is devastating and often leaves the injured individual with persistent dysfunction. The injury persists because humans have poor wound repair and there are no pharmacologic treatments to induce wound repair after SCI. The continued efforts to discover therapeutic targets and develop treatments heavily relies on animal models. The purpose of this project is to develop and study novel mammalian models of SCI to provide insights for the development and effective implementation of SCI therapies.

Lab mice (Mus musculus) are a powerful tool for recapitulating the progression and persistent damage evident in human SCI, but …

Myelin, Cpla2, And Azithromycin: Modulation Of Macrophage Activation In Spinal Cord Injury Inflammation, Timothy J. Kopper

Theses and Dissertations--Physiology

Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by macrophages consisting of resident microglia and infiltrating monocytes. These chronically activated SCI macrophages adopt a pro-inflammatory, pathological state that continues to cause additional damage after the initial injury and inhibits recovery. While the roles of macrophages in SCI pathophysiology are well documented, the factors contributing to this maladaptive response are poorly understood. Here, we identify the detrimental effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA₂) in myelin- mediated potentiation of pro-inflammatory macrophage activation. Macrophage- mediated inflammatory …

Characterization Of Spontaneous Preeclampsia In The African Green Monkey (Chlorocebus Aethiops Sabaeus), Chelsea Christina Weaver

Theses and Dissertations--Biology

Hypertensive pregnancy disorders are a major contribution to maternal and neonatal mortality worldwide. Two of these disorders, preeclampsia and chronic hypertension in pregnancy, affect up to 10% of all pregnancies. These hypertensive disorders of pregnancy are associated with long-term, postnatal risk factors for both mother and offspring. Despite numerous recent advances in preeclampsia research, the underlying mechanisms are still not understood. This could be due to lack of a spontaneous animal model. This dissertation presents the African Green Monkey (AGM; Chlorocebus aethiops sabaeus) as the first known spontaneous animal model of preeclampsia and a highly translational model of chronic …

The Tumor Suppressor Par-4 Regulates Hypertrophic Obesity, Nathalia Araujo

Theses and Dissertations--Toxicology and Cancer Biology

Prostate Apoptosis Response-4 (Par-4) is a tumor suppressor ubiquitously expressed in all tissues and able to selectively induce apoptosis in cancer cells. Although well established in the context of cancer, relatively little is known about the function of Par-4 in the healthy and non-tumorigenic context. Observations from our lab showed that Par-4 knockout mouse lines were obese and displayed adipocyte hypertrophy under a normal chow diet when compared to Par-4 wild-type mice. These Par-4 knockout mice exhibited hepatic steatosis and hyperinsulinemia as secondary consequences of obesity. Par-4 knockout mice displayed increased intestinal dietary fat absorption and its subsequent storage in …

Diverse And Complex Muscle Spindle Afferent Firing Properties Emerge From Multiscale Muscle Mechanics, Kyle P. Blum, Kenneth S. Campbell, Brian C. Horslen, Paul Nardelli, Stephen N. Housley, Timothy C. Cope, Lena H. Ting

Physiology Faculty Publications

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents – including movement history dependence, and nonlinear scaling with muscle stretch velocity – emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during …

K2p2.1 (Trek-1) Potassium Channel Activation Protects Against Hyperoxia-Induced Lung Injury, Tatiana Zyrianova, Benjamin Lopez, Riccardo Olcese, John Belperio, Christopher M. Waters, Leanne Wong, Victoria Nguyen, Sriharsha Talapaneni, Andreas Schwingshackl

Physiology Faculty Publications

No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K_2P2.1 (TREK-1) K⁺ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca …

Lung Epithelial Trpa1 Mediates Lipopolysaccharide-Induced Lung Inflammation In Bronchial Epithelial Cells And Mice, Hsin-Kuo Ko, An-Hsuan Lin, Diahn-Warng Perng, Tzong-Shyuan Lee, Yu Ru Kou

Physiology Faculty Publications

Toll-like receptor (TLR) 4 was originally thought to be the sole pattern recognition receptor for lipopolysaccharide (LPS). Transient receptor potential ankyrin 1 (TRPA1), a Ca²⁺-permeant channel, has been suggested as a non-TLR receptor membrane-bound sensor of LPS. We recently reported that TRPA1 is expressed in lung epithelial cells (LECs) and mediates lung inflammation induced by cigarette smoke. However, the role of TRPA1 in LPS-induced lung inflammation has not been conclusively defined, and its underlying cellular mechanisms remain unclear. In this study, our in vitro results showed that LPS sequentially produced a cascade of events, including the elevation of …

Ceramide Analog [18F]F-Hpa-12 Detects Sphingolipid Disbalance In The Brain Of Alzheimer’S Disease Transgenic Mice By Functioning As A Metabolic Probe, Simone M. Crivelli, Daan Van Kruining, Qian Luo, Jo A. A. Stevens, Caterina Giovagnoni, Andreas Paulus, Matthias Bauwens, Dusan Berkes, Helga E. De Vries, Monique T. Mulder, Jochen Walter, Etienne Waelkens, Rita Derua, Johannes V. Swinnen, Jonas Dehairs, Felix M. Mottaghy, Mario Losen, Erhard Bieberich, Pilar Martinez-Martinez

Physiology Faculty Publications

The metabolism of ceramides is deregulated in the brain of Alzheimer’s disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-β pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [¹⁸F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [¹⁸F]F-HPA-12 in the brain, independently from the APOE4 …

Rats Genetically Selected For High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin By Upregulation Of Hepatic Biliverdin Reductase-A (Bvra) And Suppression Of Ugt1a1, Terry D. Hinds Jr., Justin F. Creeden, Darren M. Gordon, Adam C. Spegele, Steven L. Britton, Lauren G. Koch, David E. Stec

Pharmacology and Nutritional Sciences Faculty Publications

Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome …

Efficient Cocaine Degradation By Cocaine Esterase-Loaded Red Blood Cells, Luigia Rossi, Francesca Pierigè, Marco Agostini, Noemi Bigini, Veronica Termopoli, Yingting Cai, Fang Zheng, Chang-Guo Zhan, Donald W. Landry, Mauro Magnani

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Recombinant bacterial cocaine esterase (CocE) represents a potential protein therapeutic for cocaine use disorder treatment. Unfortunately, the native enzyme was highly unstable and the corresponding mutagenized derivatives, RBP-8000 and E196-301, although improving in vitro thermo-stability and in vivo half-life, were a partial solution to the problem. For cocaine use disorder treatment, an efficient cocaine-metabolizing enzyme with a longer residence time in circulation would be needed. We investigated in vitro the possibility of developing red blood cells (RBCs) loaded with RBP-8000 and E196-301 as a biocompatible system to metabolize cocaine for a longer period of time. RBP 8000 stability within human …

Encoding The Odor Of Cigarette Smoke, Timothy S. Mcclintock, Naazneen Khan, Yelena Alimova, Madeline Aulisio, Dong Y. Han, Patrick Breheny

Physiology Faculty Publications

The encoding of odors is believed to begin as a combinatorial code consisting of distinct patterns of responses from odorant receptors (ORs), trace-amine associated receptors (TAARs), or both. To determine how specific response patterns arise requires detecting patterns in vivo and understanding how the components of an odor, which are nearly always mixtures of odorants, give rise to parts of the pattern. Cigarette smoke, a common and clinically relevant odor consisting of > 400 odorants, evokes responses from 144 ORs and 3 TAARs in freely behaving male and female mice, the first example of in vivo responses of both ORs and …

Near Simultaneous Laser Scanning Confocal And Atomic Force Microscopy (Conpokal) On Live Cells, Joree N. Sandin, Surya P. Aryal, Thomas E. Wilkop, Christopher I. Richards, Martha E. Grady

Physiology Faculty Publications

Techniques available for micro- and nano-scale mechanical characterization have exploded in the last few decades. From further development of the scanning and transmission electron microscope, to the invention of atomic force microscopy, and advances in fluorescent imaging, there have been substantial gains in technologies that enable the study of small materials. Conpokal is a portmanteau that combines confocal microscopy with atomic force microscopy (AFM), where a probe "pokes" the surface. Although each technique is extremely effective for the qualitative and/or quantitative image collection on their own, Conpokal provides the capability to test with blended fluorescence imaging and mechanical characterization. Designed …

Considerations For Studying Sex As A Biological Variable In Spinal Cord Injury, Andrew N. Stewart, Steven M. Maclean, Arnold J. Stromberg, Jessica P. Whelan, William M. Bailey, John C. Gensel, Melinda E. Wilson

Physiology Faculty Publications

In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of …

Long Qt Syndrome Type 2: Emerging Strategies For Correcting Class 2 Kcnh2 (Herg) Mutations And Identifying New Patients, Makoto Ono, Don E. Burgess, Elizabeth A. Schroder, Claude S. Elayi, Corey L. Anderson, Craig T. January, Bin Sun, Kalyan Immadisetty, Peter M. Kekenes-Huskey, Brian P. Delisle

Physiology Faculty Publications

Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies …

Circadian Disruption With Constant Light Exposure Exacerbates Atherosclerosis In Male Apolipoproteine-Deficient Mice, Jeffrey M. Chalfant, Deborah A. Howatt, Lisa R. Tannock, Alan Daugherty, Julie S. Pendergast

Biology Faculty Publications

Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE^−/−) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE^−/− mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE^−/− mice that were indistinguishable from rhythms in ApoE^+/+ mice. These data showed that ApoE^−/− mice had no inherent circadian …

Predictors Of Work Economy In Structural Firefighters, Maxwell Steele Norris

Theses and Dissertations--Kinesiology and Health Promotion

The purpose of this study was to investigate a novel work economy metric to quantify firefighter physical ability and identify physical fitness and anthropometric correlates of work economy. Physical fitness and anthropometric measurements were taken on 19 incumbent structural firefighters (Age: 35.0±7.1 yr, Body mass: 87.5±13.1 kg). Firefighters performed a timed maximal effort simulated fireground test (SFGT) in personal protective equipment. SFGT air depletion was represented by change in cylinder pressure. Work economy was quantified as: (1/(SFGT completion time x air depletion))x10⁴. Bivariate and multiple linear regression analyses were used to identify anthropometric and physical fitness predictors of …

The Role Of Melatonin In Biological Rhythms Of Songbirds, Clifford E. Harpole

Theses and Dissertations--Biology

In vertebrates, melatonin is a hormone that is produced and secreted at night and inhibited by light. This unique “darkness-only” expression profile makes it an intellectually appealing candidate for a means of transmitting temporal information to an individual, both time of day and time of year.

In passerine birds, “time of day” information is certainly transmitted via melatonin secretion. The primary producer of systemic melatonin in this family of birds is the pineal gland, and surgical removal of it causes a bird to become arrhythmic in constant conditions. I find that as pinealectomized house sparrows (Passer domesticus) become …

Divergence In Neuronal Calcium Dysregulation In Brain Aging And Animal Models Of Ad, Adam Ghoweri

Theses and Dissertations--Pharmacology and Nutritional Sciences

Neuronal calcium dysregulation first garnered attention during the mid-1980’s as a key factor in brain aging, which led to the formulation of the Ca²⁺ hypothesis of brain aging and dementia. Indeed, many Ca²⁺-dependent cellular processes that change with age, including an increase in the afterhyperpolarization, a decrease in long-term potentiation, an increased susceptibility to long-term depression, and a reduction in short-term synaptic plasticity, have been identified. It was later determined that increased intracellular Ca²⁺ with age was due to increased Ca²⁺ channel density, elevated release from intracellular Ca²⁺ stores, and decreased Ca²⁺ buffering …

Striated Muscle Specific Ribosomal Protein L3-Like: Effect Of Knockout On Cardiac Function And Protein Translation, Laura P. Brown

Theses and Dissertations--Physiology

Ribosomes are the molecular machinery of the cell that catalyzes synthesis of peptides from amino acids. The eukaryotic ribosome is made up of four strands of ribosomal RNA (rRNA) and ~80 ribosomal proteins. While many tissues routinely exhibit variations of ribosomal protein stoichiometry, tissue specific ribosomal proteins are rare. The ribosomal protein with the highest tissue specificity of any ribosomal protein is found in striated muscle, ribosomal protein L3-like (RPL3L). Other than its tissue specificity, association with atrial fibrillation, and chromosomal location, there is little known about the function of RPL3L. However, its ubiquitously expressed paralog, RPL3, has been well …

Remodeling In The Actin Core Of The Auditory Hair Cell Stereocilia As A Novel Component Of Temporary Noise-Induced Hearing Loss, Jonathan Michael Grossheim

Theses and Dissertations--Physiology

The rigid, paracrystalline actin core of auditory hair cell stereocilia is extremely stable and after initial formation must persist for the life of the cell to preserve hearing in mammals. In healthy hair cells, turnover of actin molecules occurs only in a small region near the tips of stereocilia, while the actin filaments of the shaft are stable. For decades damage to the actin core of stereocilia from acoustic trauma has only been attributed to cases of permanent noise-induced hearing loss. Here, we show that repairable actin core damage occurs in temporary noise-induced hearing loss from moderate acoustic trauma.

We …

Appetite-Regulating Hormones In Energy Compensation With Exercise, Jack Moreland

Theses and Dissertations--Nutrition and Food Systems

Background: The appetite-regulating hormones may influence compensatory increases in energy intake with exercise, although this causal relationship has been difficult to prove in a longitudinal trial.

Methods: 37 participants (29 female) aged 18 to 40 years performed aerobic exercise 6 days (6d), 2 days (2d), or 0 days per week for 12-weeks. Concentrations of ghrelin, leptin, glucagon-like peptide 1 (GLP-1), and insulin were assessed before (fasting, minute 0) and after a standardized meal at minute 15, 30, 45, 60, 90, 120, 150, and 180. Linear mixed-effects models were used to model the relationships between time point (12 weeks vs. baseline) …

Modulation Of Epileptogenesis: A Paradigm For The Integration Of Enzyme-Based Microelectrode Arrays And Optogenetics, Corwin R. Butler, Jeffery A. Boychuk, Francois Pomerleau, Ramona Alcala, Peter Huettl, Yi Ai, Johan Jakobsson, Sidney W. Whiteheart, Greg A. Gerhardt, Bret N. Smith, John T. Slevin

Physiology Faculty Publications

BACKGROUND: Genesis of acquired epilepsy includes transformations spanning genetic-to- network-level modifications, disrupting the regional excitatory/inhibitory balance. Methodology concurrently tracking changes at multiple levels is lacking. Here, viral vectors are used to differentially express two opsin proteins in neuronal populations within dentate gyrus (DG) of hippocampus. When activated, these opsins induced excitatory or inhibitory neural output that differentially affected neural networks and epileptogenesis. In vivo measures included behavioral observation coupled to real-time measures of regional glutamate flux using ceramic-based amperometric microelectrode arrays (MEAs).

RESULTS: Using MEA technology, phasic increases of extracellular glutamate were recorded immediately upon application of blue light/488 nm …

Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito

Physiology Faculty Publications

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of …

Post-Acquisition Processing Confounds In Brain Volumetric Quantification Of White Matter Hyperintensities, Ahmed A. Bahrani, Omar M. Al-Janabi, Erin L. Abner, Shoshana H. Bardach, Richard J. Kryscio, Donna M. Wilcock, Charles D. Smith, Gregory A. Jicha

Neurology Faculty Publications

BACKGROUND: Disparate research sites using identical or near-identical magnetic resonance imaging (MRI) acquisition techniques often produce results that demonstrate significant variability regarding volumetric quantification of white matter hyperintensities (WMH) in the aging population. The sources of such variability have not previously been fully explored.

NEW METHOD: 3D FLAIR sequences from a group of randomly selected aged subjects were analyzed to identify sources-of-variability in post-acquisition processing that can be problematic when comparing WMH volumetric data across disparate sites. The methods developed focused on standardizing post-acquisition protocol processing methods to develop a protocol with less than 0.5% inter-rater variance.

RESULTS: A series …

Downregulation Of Orco And 5-Htt Alters Nestmate Discrimination In The Subterranean Termite Ondontotermes Formosanus (Shiraki), Pengdong Sun, Shuxin Yu, Austin Merchant, Chaoliang Lei, Xuguo Zhou, Qiuying Huang

Entomology Faculty Publications

Nestmate discrimination allows social insects to recognize nestmates from non-nestmates using colony-specific chemosensory cues, which typically evoke aggressive behavior toward non-nestmates. Functional analysis of genes associated with nestmate discrimination has been primarily focused on inter-colonial discrimination in Hymenopterans, and parallel studies in termites, however, are grossly lacking. To fill this gap, we investigated the role of two genes, Orco and 5-HTT, associated with chemosensation and neurotransmission respectively, in nestmate discrimination in a highly eusocial subterranean termite, Odontotermes formosanus (Shiraki). We hypothesized that knocking down of these genes will compromise the nestmate recognition and lead to the antagonistic behavior. To …

Stimulatory Effect Of 5-Hydroxytryptamine (5-Ht) On Rat Capsaicin-Sensitive Lung Vagal Sensory Neurons Via Activation Of 5-Ht3 Receptors, Chun-Chun Hsu, Ting Ruan, Lu-Yuan Lee, You Shuei Lin

Physiology Faculty Publications

5-hydroxytryptamine (5-HT) is an inflammatory mediator known to be released in lung. Capsaicin-sensitive lung vagal (CSLV) afferents function as a primary sensor for detecting chemical stimuli and produce consequent reflexes during lung inflammation. To characterize the effect of 5-HT on CSLV afferents, responses of cardiorespiratory reflexes and single-unit C-fiber afferents to right-atrial injections of 5-HT were investigated in anesthetized Sprague-Dawley rats. Bolus injection of 5-HT (8 μg/kg) caused an immediate augmented breath and apnea, accompanied by hypotension and bradycardia. These initial responses were then followed by a brief pressor response and a more sustained depressor response. After a perineural treatment …

Facilitation Of Neuropathic Pain By The Npy Y1 Receptor-Expressing Subpopulation Of Excitatory Interneurons In The Dorsal Horn, Tyler S. Nelson, Weisi Fu, Renee R. Donahue, Gregory F. Corder, Tomas Hökfelt, Ronald G. Wiley, Bradley K. Taylor

Physiology Faculty Publications

Endogenous neuropeptide Y (NPY) exerts long-lasting spinal inhibitory control of neuropathic pain, but its mechanism of action is complicated by the expression of its receptors at multiple sites in the dorsal horn: NPY Y1 receptors (Y1Rs) on post-synaptic neurons and both Y1Rs and Y2Rs at the central terminals of primary afferents. We found that Y1R-expressing spinal neurons contain multiple markers of excitatory but not inhibitory interneurons in the rat superficial dorsal horn. To test the relevance of this spinal population to the development and/or maintenance of acute and neuropathic pain, we selectively ablated Y1R-expressing interneurons with intrathecal administration of an …

Macrolide Derivatives Reduce Proinflammatory Macrophage Activation And Macrophage‐Mediated Neurotoxicity, Bei Zhang, Timothy J. Kopper, Xiaodong Liu, Zheng Cui, Steven G. Van Lanen, John C. Gensel

Physiology Faculty Publications

Introduction: Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent.

Aims: To improve the efficacy and reduce antibiotic resistance risk of AZM‐based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow‐derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF‐gamma) with and without derivative costimulation. Pro‐ and anti‐inflammatory cytokine production, IL‐12 and IL‐10, respectively, was quantified using ELISA. Neuron culture …