Medical Neurobiology Commons^™

Effect Of Synthetic Aβ Peptide Oligomers And Fluorinated Solvents On Kv1.3 Channel Properties And Membrane Conductance, Maria I. Lioudyno, Matteo Broccio, Yuri Sokolov, Suhail Rasool, Jessica Wu, Michael T. Alkire, Virginia Liu, J. Ashot Kozak, Philip R. Dennison, Charles G. Glabe, Mathias Lösche, James E. Hall

Neuroscience, Cell Biology & Physiology Faculty Publications

The impact of synthetic amyloid β (1–42) (Aβ_1–42) oligomers on biophysical properties of voltage-gated potassium channels Kv 1.3 and lipid bilayer membranes (BLMs) was quantified for protocols using hexafluoroisopropanol (HFIP) or sodium hydroxide (NaOH) as solvents prior to initiating the oligomer formation. Regardless of the solvent used Aβ_1–42 samples contained oligomers that reacted with the conformation-specific antibodies A11 and OC and had similar size distributions as determined by dynamic light scattering. Patch-clamp recordings of the potassium currents showed that synthetic Aβ_1–42 oligomers accelerate the activation and inactivation kinetics of Kv 1.3 current with no significant effect …

Parkinson’S Disease: Molecular Mechanisms And Treatments, Delia Vahey

Senior Honors Theses

Parkinson’s disease is a motor system disorder that is caused primarily by the loss of dopamine-producing brain cells. The most affected brain structure is the pars compacta of the substantia nigra. This area of the brain is essential to the control of voluntary movement, and so its impairment leads to symptoms such as tremors, rigidity, and impaired balance. The neuronal protein alpha-synuclein has been shown to be heavily involved in the pathogenesis of the disease at the cellular level. The currently available treatments for PD mainly target dopamine regulation, and there been no cure developed for the disease at present. …

Hyccin, The Molecule Mutated In The Leukodystrophy Hypomyelination And Congenital Cataract (Hcc), Is A Neuronal Protein., Elisabetta Gazzerro, Simona Baldassari, Caterina Giacomini, Veronica Musante, Floriana Fruscione, Veronica La Padula, Roberta Biancheri, Sonia Scarfì, Valeria Prada, Federica Sotgia, Ian D Duncan, Federico Zara, Hauke B Werner, Michael P Lisanti, Lucilla Nobbio, Anna Corradi, Carlo Minetti

Kimmel Cancer Center Faculty Papers

"Hypomyelination and Congenital Cataract", HCC (MIM #610532), is an autosomal recessive disorder characterized by congenital cataract and diffuse cerebral and peripheral hypomyelination. HCC is caused by deficiency of Hyccin, a protein whose biological role has not been clarified yet. Since the identification of the cell types expressing a protein of unknown function can contribute to define the physiological context in which the molecule is explicating its function, we analyzed the pattern of Hyccin expression in the central and peripheral nervous system (CNS and PNS). Using heterozygous mice expressing the b-galactosidase (LacZ) gene under control of the Hyccin gene regulatory elements, …

Active Site Mutations Change The Cleavage Specificity Of Neprilysin., Travis Sexton, Lisa J. Hitchcook, David W. Rodgers, Luke H. Bradley, Louis B. Hersh

Molecular and Cellular Biochemistry Faculty Publications

Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe⁵⁶³ and Ser⁵⁴⁶. Among the mutants studied in detail we observed changes in their activity towards leucine⁵-enkephalin, insulin B chain, and amyloid β_1-40. For example, NEP^F563I displayed an increase in preference towards cleaving leucine⁵-enkephalin relative to insulin B chain, while mutant NEP^S546E was less discriminating …

Early Versus Delayed Decompression For Traumatic Cervical Spinal Cord Injury: Results Of The Surgical Timing In Acute Spinal Cord Injury Study (Stascis), Michael G. Fehlings, Alexander Vaccaro, Jefferson R. Wilson, Anoushka Singh, David W. Cadotte, James S. Harrop, Bizhan Aarabi, Christopher Shaffrey, Marcel Dvorak, Charles Fisher, Paul Arnold, Eric M. Massicotte, Stephen Lewis, Raja Rampersaud

Department of Neurosurgery Faculty Papers

Background: There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (,24 hours after injury) versus late ($24 hours after injury) decompressive surgery after traumatic cervical SCI.

Methods: We performed a multicenter, international, prospective cohort study (Surgical Timing in Acute Spinal Cord Injury Study: STASCIS) in adults aged 16–80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was …

Ginkgo Extract Egb761 Confers Neuroprotection By Reduction Of Glutamate Release In Ischemic Brain, Alexander Mdzinarishvili, Rachita K. Sumbria, Dorothee Lang, Jochen Klein

Pharmacy Faculty Articles and Research

Purpose - Ginkgo extract EGb761 has shown anti-edema and anti-ischemic effects in various experimental models. In the present study, we demonstrate neuroprotective effects of EGb761 in experimental stroke while monitoring brain metabolism by microdialysis. Methods - We have used oxygen-glucose deprivation in brain slices in vitro and middle cerebral artery occlusion (MCAO) in vivo to induce ischemia in mouse brain. We used microdialysis in mouse striatum to monitor extracellular concentrations of glucose and glutamate. Results - In vitro, EGb761 reduced ischemia-induced cell swelling in hippocampal slices by 60%. In vivo, administration of EGb761 (300 mg/kg) reduced cell degeneration and edema …

Loss Of Renal Allografts Secondary To Candida Vascular Complications In Two Recipients From The Same Donor, Govardhana R. Yannam, Lucile E. Wrenshall, R. Brian Stevens

Neuroscience, Cell Biology & Physiology Faculty Publications

Infections remain a major cause of morbidity and mortality in transplant patients. Organ recipients are also susceptible to donor-derived pathogens and the majority of donor infections are easily treatable. Rarely, some pathogens have produced life-threatening complications by compromising the vascular anastomosis. In this case series we report loss of two kidney allografts secondary to vascular complications due to Candida albicans. Both recipients received grafts from a common donor, in whom Candida bacteremia in the donor was not apparent at the time of organ acceptance but became apparent on delayed cultures.

Electronic Nose Based On Independent Component Analysis Combined With Partial Least Squares And Artificial Neural Networks For Wine Prediction, Teodoro Aguilera, Jesús Lozano, José A. Paredes, Francisco J. Alvarez, José I. Suárez

Neuroscience, Cell Biology & Physiology Faculty Publications

The aim of this work is to propose an alternative way for wine classification and prediction based on an electronic nose (e-nose) combined with Independent Component Analysis (ICA) as a dimensionality reduction technique, Partial Least Squares (PLS) to predict sensorial descriptors and Artificial Neural Networks (ANNs) for classification purpose. A total of 26 wines from different regions, varieties and elaboration processes have been analyzed with an e-nose and tasted by a sensory panel. Successful results have been obtained in most cases for prediction and classification.

Electrophysiological Abnormalities In Sod1 Transgenic Models In Amyotrophic Lateral Sclerosis: The Commonalities And Differences, Sherif M. Elbasiouny, Katharina Quinlan, Tahra L. Eissa, Charles J. Heckman

Neuroscience, Cell Biology & Physiology Faculty Publications

Since its first description in 1874 by Charcot, the hallmark feature of ALS is the progressive degeneration of upper and lower motoneurons (Charcot, 1874). In the spinal cord, motoneuron degeneration starts long before symptom onset and advances in a size-related fashion, in which large-size alpha-motoneurons degenerate first followed by small-size alpha-motoneurons (Pun et al., 2006; Hegedus et al., 2007; Hegedus et al., 2008). There are conflicting reports regarding the survival of the smallest-sized spinal motoneurons, the gamma-motoneurons (Swash and Fox, 1974; Sobue et al., 1981). Despite its original description, the neuronal degeneration in ALS is not limited to motoneurons. Recent …

Loss Of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration And Alzheimer's Disease-Related Tau Phosphorylation Via Par-1., Kanae Iijima-Ando, Michiko Sekiya, Akiko Maruko-Otake, Yosuke Ohtake, Emiko Suzuki, Bingwei Lu, Koichi M Iijima

Farber Institute for Neuroscience Faculty Papers

Abnormal phosphorylation and toxicity of a microtubule-associated protein tau are involved in the pathogenesis of Alzheimer's disease (AD); however, what pathological conditions trigger tau abnormality in AD is not fully understood. A reduction in the number of mitochondria in the axon has been implicated in AD. In this study, we investigated whether and how loss of axonal mitochondria promotes tau phosphorylation and toxicity in vivo. Using transgenic Drosophila expressing human tau, we found that RNAi-mediated knockdown of milton or Miro, an adaptor protein essential for axonal transport of mitochondria, enhanced human tau-induced neurodegeneration. Tau phosphorylation at an AD-related site Ser262 …

Disruptions In The Regulation Of Extracellular Glutamate In The Rat Central Nervous System After Diffuse Brain Injury, Jason Michael Hinzman

Theses and Dissertations--Neuroscience

Glutamate, the predominant excitatory neurotransmitter in the central nervous system, is involved in almost all aspects of neurological function including cognition, motor function, memory, learning, decision making, and neuronal plasticity. For normal neurological function, glutamate signaling must be properly regulated. Disrupted glutamate regulation plays a pivotal role in the acute pathophysiology of traumatic brain injury (TBI), disrupting neuronal signaling, initiating secondary injury cascades, and producing excitotoxicity. Increases in extracellular glutamate have been correlated with unfavorable outcomes in TBI survivors, emphasizing the importance of glutamate regulation.

The aim of this thesis was to examine disruptions in the regulation of extracellular glutamate …

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 …

Prion Characterization Using Cell Based Approaches, Vadim Khaychuk

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Prions are the causative agents of a group of lethal, neurodegenerative conditions that include sheep scrapie, bovine spongiform encephalopathy (BSE), and human Creutzfeldt-Jakob disease (CJD). Prions are derived from the conversion of a normal, primarily alpha-helical, cellular prion protein (PrP^C), to an infectious, beta sheet-rich conformer (PrP^Sc). Many unresolved issues surround the process of PrP conversion, and we know very little about cellular responses to these unique pathogens. Our lack of knowledge relates, in part, to the difficulty of infecting cells in vitro with prions. While expression of PrP^C is an absolute requirement for prion …

Translating Quality To The Bedside: Collaboration Improves Patient Outcomes, Maureen T. Smith Msn, Rn, Cnrn

Patient Care Services / Nursing

No abstract provided.

Msh2 Acts In Medium-Spiny Striatal Neurons As An Enhancer Of Cag Instability And Mutant Huntingtin Phenotypes In Huntington's Disease Knock-In Mice., Marina Kovalenko, Ella Dragileva, Jason St Claire, Tammy Gillis, Jolene R Guide, Jaclyn New, Hualing Dong, Raju Kucherlapati, Melanie H Kucherlapati, Michelle E Ehrlich, Jong-Min Lee, Vanessa C Wheeler

Farber Institute for Neuroscience Faculty Papers

The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT) exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR) pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111) with mice carrying a conditional (floxed) Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs …

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 …

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 …