Medical Sciences Commons^™

Triterpenoid Modulation Of Il-17 And Nrf-2 Expression Ameliorates Neuroinflammation And Promotes Remyelination In Autoimmune Encephalomyelitis, Tej K. Pareek, Abdelmadjid Belkadi, Sashi Kesavapany, Anita Zaremba, Sook L. Loh, Lianhua Bai, Mark L. Cohen, Colin Meyer, Karen T. Liby, Robert H. Miller, Michael B. Sporn, John J. Letterio

Dartmouth Scholarship

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of …

An Evaluation Of Neuroplasticity And Behavior After Deep Brain Stimulation Of The Nucleus Accumbens In An Animal Model Of Depression., Steven M Falowski, Ashwini Sharan, Beverly A S Reyes, Carl Sikkema, Patricia Szot, Elisabeth J Van Bockstaele

Department of Neurosurgery Faculty Papers

BACKGROUND: Recent interest has demonstrated the nucleus accumbens (NAcc) as a potential target for the treatment of depression with deep brain stimulation (DBS).

OBJECTIVE: To demonstrate that DBS of the NAcc is an effective treatment modality for depression and that chemical and structural changes associated with these behavioral changes are markers of neuroplasticity.

METHODS: A deep brain stimulator was placed in the NAcc of male Wistar-Kyoto rats. Groups were divided into sham (no stimulation), intermittent (3 h/d for 2 weeks), or continuous (constant stimulation for 2 weeks). Exploratory and anxietylike behaviors were evaluated with the open-field test before and after …

The Electrophysiological And Neuropsychological Organization Of Long Term Memory, Richard J. Addante

Psychology Faculty Publications

The electrophysiological correlates of recognition memory retrieval were examined in order to identify the neural conditions that precede accurate memory retrieval, characterize the processes that contribute to high and low confidence memory responses, and determine which memory processes are impaired after brain injury. Human electroencephalogram (EEG) was recorded during recognition confidence and source memory judgments in three experiments. In Experiment 1, mid-frontal pre-stimulus theta oscillations were found to precede the stimulus presentation of items that were successfully recollected, but they were not found to be predictive of item familiarity. Moreover, during stimulus presentation, recollection was associated with an increase in …

Introducing Functional Data Analysis To Neuroimaging, And Vice Versa, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Functional Recovery Of Untreated Human Immunodeficiency Virus-Associated Guillain-Barré Syndrome: A Case Report, Adam L. Schreiber, John W. Norbury Iii, Eduardo A. De Sousa

Department of Rehabilitation Medicine Faculty Papers

HIV-associated Guillain-Barré Syndrome is a well-documented phenomenon, typically occurring at seroconversion. GBS may result in functional impairment treated with a combination of medications, plasmapheresis, and rehabilitation. The quantified functional recovery of HIV-associated GBS with or without HIV treatment is not well-described. Utilizing serial FIM scoring, we describe a patient’s recovery from HIV-associated GBS after treatment with IVIg and acute inpatient rehabilitation without HIV treatment.

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 …

Intratracheal Instillation Of Cerium Oxide Nanoparticles Induces Hepatic Toxicity In Male Sprague-Dawley Rats, Siva Krishna Nalabotu, Madhukar Babu Kolli, William E. Triest, Jane Y. Ma, Nandini Dpk Manne, Anjaiah Katta, Hari S. Addagarla, Kevin M. Rice, Eric R. Blough

MIIR Faculty Research

Background: Cerium oxide (CeO₂) nanoparticles have been posited to have both beneficial and toxic effects on biological systems. Herein, we examine if a single intratracheal instillation of CeO₂ nanoparticles is associated with systemic toxicity in male Sprague-Dawley rats.

Methods and results: Compared with control animals, CeO₂ nanoparticle exposure was associated with increased liver ceria levels, elevations in serum alanine transaminase levels, reduced albumin levels, a diminished sodium-potassium ratio, and decreased serum triglyceride levels (P < 0.05). Consistent with these data, rats exposed to CeO₂nanoparticles also exhibited reductions in liver weight (P < 0.05) and dose-dependent hydropic degeneration, hepatocyte enlargement, sinusoidal dilatation, and accumulation of granular material. No histopathological alterations were observed in the kidney, spleen, and heart. Analysis of serum biomarkers suggested an elevation of acute phase reactants and markers of hepatocyte injury in the rats exposed to CeO₂ nanoparticles.

Conclusion: Taken together, these data suggest that intratracheal instillation …

Disclosure Of Clinical Trial Results When Product Development Is Abandoned, Michael A. Rogawski, Howard J. Federoff

Michael A. Rogawski

Currently, sponsors are not required to report the outcomes of clinical research on drugs or devices that do not lead to an approved product. Consequently, the public cannot benefit from scientific information derived from all failed or abandoned drugs and devices. Provisions in the U.S. Food and Drug Administration Amendments Act of 2007 provide an opportunity for the Department of Health and Human Services to rectify this situation. By reporting the results of clinical trials of abandoned products in a publicly accessible database and in the peer-reviewed journal literature, sponsors would satisfy a core ethical obligation of clinical research and …

The Role Of The Androgen Receptor Cofactor P44/Wdr77 In Astrocyte Activation, Bryce H. Vincent

Dissertations & Theses (Open Access)

Astrogliosis is induced by neuronal damage and is also a pathological feature of the major aging-related neurodegenerative disorders. The mechanisms that control the cascade of astrogliosis have not been well established. In a previous study, we identified a novel androgen receptor (AR)-interacting protein (p44/WDR77) and found that it plays a critical role in the control of proliferation and differentiation of prostate epithelial cells. In the present study, we found that deletion of the p44 gene in the mouse brain caused accelerated aging with dramatic astrogliosis. The p44/WDR77 is expressed in astrocytes and loss of p44/WDR77 expression in astrocytes leads to …

11beta-Hydroxylase Inhibitors Protect Against Seizures In Mice By Increasing Endogenous Neurosteroid Synthesis, Rafal Kaminski, Michael Rogawski

Michael A. Rogawski

Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABA-A receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but …

Patterns Of Fetal Heart Rate Response At ∼30 Weeks Gestation Predict Size At Birth, C. Sandman, C. J. Cordova, E. P. Davis, Laura M. Glynn, C. Buss

Psychology Faculty Articles and Research

There is evidence that fetal exposure to maternal stress is associated with adverse birth outcomes. Less is known about the association between fetal responses to a stressor and indicators of fetal maturity and developmental outcomes. The purpose of the present study was to determine whether fetal heart rate (FHR) patterns in response to a startling stimulus at ∼30 weeks of gestation were associated with gestational age at birth and birth weight. FHR was measured in 156 maternal–fetal dyads following a vibroacoustic stimulus. All pregnancies were singleton intrauterine pregnancies in English-speaking women who were primarily married, middle class, White and at …

Acute Effects Of A Selective Cannabinoid-2 Receptor Agonist On Neuroinflammation In A Model Of Traumatic Brain Injury., Melanie B Elliott, Ronald F Tuma, Peter S Amenta, Mary F Barbe, Jack I Jallo

Department of Neurosurgery Faculty Papers

Proposed therapeutic strategies for attenuating secondary traumatic brain injury (TBI) include modulation of acute neuroimmune responses. The goal of this study was to examine the acute effects of cannabinoid-2 receptor (CB(2)R) modulation on behavioral deficits, cerebral edema, perivascular substance P, and macrophage/microglial activation in a murine model of TBI. Thirty male C57BL/6 mice underwent sham surgery, or cortical contusion impact injury (CCI). CCI mice received vehicle or the CB(2)R agonist 0-1966 at 1 and 24 h after injury. Performance on the rotarod, forelimb cylinder, and open-field tests were evaluated before and at 48 h after sham or CCI surgery. Cerebral …

A Phase I/Iia Clinical Trial Of A Recombinant Rho Protein Antagonist In Acute Spinal Cord Injury., Michael G Fehlings, Nicholas Theodore, James Harrop, Gilles Maurais, Charles Kuntz, Chris I Shaffrey, Brian K Kwon, Jens Chapman, Albert Yee, Allyson Tighe, Lisa Mckerracher

Department of Neurosurgery Faculty Papers

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or …

Noise, Delays, And Resonance In A Neural Network, Austin Quan

HMC Senior Theses

A stochastic-delay differential equation (SDDE) model of a small neural network with recurrent inhibition is presented and analyzed. The model exhibits unexpected transient behavior: oscillations that occur at the boundary of the basins of attraction when the system is bistable. These are known as delay-induced transitory oscillations (DITOs). This behavior is analyzed in the context of stochastic resonance, an unintuitive, though widely researched phenomenon in physical bistable systems where noise can play in constructive role in strengthening an input signal. A method for modeling the dynamics using a probabilistic three-state model is proposed, and supported with numerical evidence. The potential …

Massively Parallel Nonparametrics [Hds 2011 Slides], Philip T. Reiss, Lei Huang

Philip T. Reiss

No abstract provided.

The Effect Of Training On Motoneuron Survival In Amyotrophic Lateral Sclerosis: Which Motoneuron Type Is Saved?, Sherif M. Elbasiouny, Jenna E. Schuster

Neuroscience, Cell Biology & Physiology Faculty Publications

Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive degeneration of motoneurons (MNs). Although the etiology of the disease is unknown, glutamate toxicity and reactive oxygen species toxicity have been strongly implicated in ALS pathophysiology, Training exercise has been proposed to provide a beneficial therapy during the early or late stages of ALS; however, some studies showed deleterious effects of exercise on survival in ALS.

Nanotubes As Mitochondrial Uncouplers, Patrick G. Sullivan

Neuroscience Faculty Patents

A method of uncoupling mitochondria in a subject including administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying is provided. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca²⁺ into mitochondria is provided, including administering a pharmaceutically effective amount of nanotubes into the subject. A method of reducing weight, treating cancer, reducing the effects of traumatic brain injury, or reducing the effects of ageing, in a subject including administering a pharmaceutically effective amount of nanotubes into the subject is also provided.

Characterization Of Amino Acid Residues Integral To Neuronal Binding Of Amyloid Beta Protein In Alzheimer’S Disease, Nicole C. Olson

Chemistry and Biochemistry

Purpose: Alzheimer’s Disease is a neurodegenerative disease resulting from over-production and neuronal accumulation of amyloid-beta proteins (Aβ40/Aβ42). The glycine residue at position 33 and histidine residues at positions 13 and 14 are involved with binding and internalization of these proteins, actions potentially inhibited by substituting or sterically hindering these residues with an antibody specific to positions 2-11 (IgG-4.1). Rat pheochromocytoma (PC12) cells differentiated with nerve growth factor were used as a neuronal model to determine whether substitution and/or antibody block amyloid-beta’s neuronal interactions.

Methods: PC12 cells were incubated with fluorescein-labeled-amyloid-beta-40 (F-Aβ40) or substituted F-Aβ40 derivatives (F-Aβ40-H13,14G, F-Aβ40-H13,14G;G33A), with or without …

Flexible Dependence Of Functional Responses On Scalar Predictors, Philip T. Reiss, Lei Huang

Philip T. Reiss

No abstract provided.

Proteomic Assessment Of A Cell Model Of Spinal Muscular Atrophy., Chia-Yen Wu, Dosh Whye, Lisa Glazewski, Leila Choe, Douglas Kerr, Kelvin H Lee, Robert W Mason, Wenlan Wang

Department of Pediatrics Faculty Papers

BACKGROUND: Deletion or mutation(s) of the survival motor neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), a neuromuscular disease characterized by spinal motor neuron death and muscle paralysis. Complete loss of the SMN protein is embryonically lethal, yet reduced levels of this protein result in selective death of motor neurons. Why motor neurons are specifically targeted by SMN deficiency remains to be determined. In this study, embryonic stem (ES) cells derived from a severe SMA mouse model were differentiated into motor neurons in vitro by addition of retinoic acid and sonic hedgehog agonist. Proteomic and western blot analyses were …

Activation Of The Basolateral Membrane Cl- Conductance Essential For Electrogenic K+ Secretion Suppresses Electrogenic Cl- Secretion, Quanhua He, Susan T. Halm, Jin Zhang, Dan R. Halm

Neuroscience, Cell Biology & Physiology Faculty Publications

Adrenaline activates transient Cl^--secretion and sustained K⁺-secretion across isolated distal colonic mucosa of guinea pig. The Ca⁺⁺-activated Cl^- channel inhibitor CaCCinh-A01 [30μM] significantly reduced electrogenic K⁺-secretion, detected as short-circuit current (I_sc). This inhibition supported the cell model for K⁺-secretion in which basolateral membrane Cl^- channels provide an exit pathway for Cl^- entering the cell via Na⁺/K⁺/2Cl^--cotransporters. CaCCinh-A01 inhibited both I_sc and transepithelial conductance in a concentration dependent manner, IC₅₀ = 6.3 μM. GlyH-101, another Cl^- channel …

Fus Transgenic Rats Develop The Phenotypes Of Amyotrophic Lateral Sclerosis And Frontotemporal Lobar Degeneration., Cao Huang, Hongxia Zhou, Jianbin Tong, Han Chen, Yong-Jian Liu, Dian Wang, Xiaotao Wei, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and …

Revisiting Ampa Receptors As An Antiepileptic Drug Target, Michael A. Rogawski

Michael A. Rogawski

In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As …

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 …

Genome-Wide Association Studies At The Interface Of Alzheimer’S Disease And Epidemiologically Related Disorders, Christopher Ryan Simmons

University of Kentucky Doctoral Dissertations

Genome-wide association studies (GWAS)s provide an unbiased means of exploring the landscape of complex genetic disease. As such, these studies have identified genetic variants that are robustly associated with a multitude of conditions. I hypothesize that these genetic variants serve as excellent tools for evaluation of the genetic interface between epidemiologically related conditions. Herein, I test the association between SNPs associated with either (i) plasma lipids, (ii) rheumatoid arthritis (RA) or (iii) diabetes mellitus (DM) and late-onset Alzheimer’s disease (AD) to identify shared genetic variants. Regarding the most significantly AD-associated variants, I have also attempted to elucidate their molecular function. …

The Faculty For Undergraduate Neuroscience: Learning Lessons Since 1991, Eric P. Wiertelak, Julio J. Ramirez, Jennifer R. Yates

Eric Wiertelak

No abstract provided.

Toward A Mechanistic Understanding Of Narcolepsy With Cataplexy, William Mccurdy

McNair Poster Presentations

Narcolepsy (hypersomnolence) is a disorder that affects 1 in 2000 individuals in the United States and it is characterized by excessive daytime sleepiness (EDS) and catalepsy, which is a sudden loss of muscle tone. As of relatively recent years, there has been a general consensus amongst the scientific community concerning the etiology of narcolepsy as numerous studies suggest that it is caused by the deficiency of neurotransmitters called orexin-A and orexin-B (or hypocretin-1 and hypocretin-2). Research suggests that deficiencies of these proteins are related to a mutation on chromosome 6 in the human leukocyte antigen (HLA) complex which is a …

The Effect Of Spiritualism On The Neuropsychological Function Of Memory, Carla Farcello

McNair Poster Presentations

The amount of physiological-neurological research performed over the past few years has dramatically increased due to our ability to view the structure and function of the brain in living human beings. The use of imaging tools has resulted in huge strides forward in unlocking some of the mysteries of the 3 pound universe-the human brain. One of the more unique neural processes being recently addressed is the affect of belief and spiritualism-the sense of being connected to something larger than oneself-on the human brain. This study hypothesized that better memory will be documented among the experimental group who report being …

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 …

Perinatal Or Adult Nf1 Inactivation Using Tamoxifen-Inducible Plpcre Each Cause Neurofibroma Formation, Debra A. Mayes, Tilat A. Rizvi, Jose A. Cancelas, Nathan T. Kolasinski, Georgianne M. Ciraolo, Anat O. Stemmer-Rachamimov, Nancy Ratner

Neuroscience, Cell Biology & Physiology Faculty Publications

OBJECTIVES

Neurofibromas are tumors initiated by biallelic mutation of the NF1 tumor suppressor gene in the Schwann cell lineage. One idea within the field suggests that Nf1loss must occur within progenitor cells present within a critical window during Schwann cell development in order for neurofibromas to form. To test this hypothesis and to examine whethermyelinating Schwann cells can serve as aneurofibroma cell of origin, Nf1 loss was induced at perinatal or adult timepoints using a tamoxifen-inducible Plp-CreERT driver.

RESULTS

Perinatal loss of Nf1 resulted in small neurofibromas late in life, while adult loss caused large neurofibromas and morbidity beginning …