Pharmacology, Toxicology and Environmental Health Commons^™

Open Neuroscience Initiative, Austin Lim

College of Science and Health Full Text Publications

The Open Neuroscience Initiative is a free-to-use textbook

This project began as a means to overcoming the financial burden that face undergraduate neuroscience students when buying textbooks. By compiling and writing a completely free-to-access textbook that covers the foundations of a typical college introduction to neuroscience course, students would have one less obstacle to overcome in their educational career, allowing them to focus their valuable time and attention on learning rather than finances. To make this project a reality, I began with a humble tweet in May 2019 that managed to gain a tiny bit of traction among the neuroscience …

Amylin As A Potential Link Between Type 2 Diabetes And Alzheimer Disease, Florin Despa, Larry B. Goldstein, Geert Jan Biessels

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Is Hyperbaric Oxygen Therapy Effective For Treating Autism?, Malky Meyer

The Science Journal of the Lander College of Arts and Sciences

Autism spectrum disorder (ASD) is characterized as a developmental disability caused by abnormalities in brain function. Studies link ASD with various physiological abnormalities, such as cerebral hypoperfusion, oxidative stress, inflammation, and mitochondrial dysfunction. Studies show that diminished blood flow to the brain demonstrates a connection between several core autistic behaviors, and the hypoperfusion generally worsen with age, growing more prevalent in older children. Although hyperbaric oxygen therapy (“HBOT”) is not yet approved by the United States Food and Drug Administration ) (“FDA”), several studies performed internationally have proven its efficacy in treating people with autism. Even so, the FDA does …

What Role Does Age-Associated Neuroplasticity Play In The Efficacy Of Cochlear Implantation?, Jacob Fliegelman

The Science Journal of the Lander College of Arts and Sciences

Bilateral, profound-severe, congenital deafness causes widespread structural and functional changes of the auditory system. In humans, the consequences of these changes are extensive and often include detriments to language acquisition and auditory perception. Fortunately, early intervention methods, such as cochlear implantation, can significantly mitigate inevitable auditory deficiencies. This review begins by briefly addressing early stages of brain development and associated anatomical discrepancies observed in congenitally deaf subjects. Considering the deleterious effects of congenital deafness, neuroplasticity, the ability of the brain to rewire itself, is of paramount importance in reversing the auditory impairments. Hence, its incorporation into the methods required for …

The Effects Of Fetal Microchimerism On Maternal Health, Matti Miller

The Science Journal of the Lander College of Arts and Sciences

No abstract provided.

Measuring Functional Brain Recovery In Regenerating Planarians By Assessing The Behavioral Response To The Cholinergic Compound Cytisine, Oné R. Pagán, Debra L. Baker, Sean Deats, Mary O'Brien, Rochelle Dymond, Gabriella Demichele

Biology Faculty Publications

Planarians are traditional model invertebrates in regeneration and developmental biology research that also display a variety of quantifiable behaviors useful to screen for pharmacologically active compounds. One such behavior is the expression of seizure-like movements (pSLMs) induced by a variety of substances. Previous work from our laboratory showed that cocaine, but not nicotine, induced pSLMs in intact but not decapitated planarians. Interestingly, as decapitated planarians regenerated their heads, they gradually recovered their sensitivity to cocaine. These results suggested a method to assess planarian brain regeneration and a possible way of identifying compounds that could enhance or hold back brain regeneration. …

The Effects Of Rf-Emf On The Child Brain, Aaron Skaist

The Science Journal of the Lander College of Arts and Sciences

It has long been debated whether or not cell phones have a deleterious effect on the brain. Recent studies indicate that the electro-magnetic field emitted by cell phones called RF-EMF is linked to cancer. Guidelines created to limit the exposure have not been changed since 1981 and do not consider children. The mechanism thought to cause cancer is reactive oxygen species (ROS), which cause the creation of micronuclei. RF-EMF poses a greater threat to children than adults. This is due to the major anatomical differences between the head of a child and an adult. The skull of a child is …

Endorphins, Endocannabinoids And Runners’ High, Elisheva Winiarz

The Science Journal of the Lander College of Arts and Sciences

Modern science takes at face value the fact that exercise is beneficial for man’s health. In recent years, medical health professionals have begun to harness exercise as a treatment for a broader range of maladies. Since various studies found increased exercise to correlate with higher levels of endorphins, most believed that the endorphins were directly responsible for what the vernacular dubbed “Runner’s High.” Scientists have sought to either augment or wholly disprove the endorphin hypothesis with further studies. Major Depressive Disorder, or MDD, is an affective condition affecting a significant portion of the general population. Aerobic exercise is increasingly being …

Analysis Of Synthetic Opioids In Postmortem Blood, Vitreous Humor, And Brain Tissue, Rachel K. Chesser

Student Theses

In the United States, the use of new synthetic opioids (e.g. fentanyl and derivatives) has become an increasing health issue with thousands of overdose deaths being observed since 2013. With the high mortality rate associated with these substances, postmortem analyses and interpretation of synthetic opioids has become extremely important. However, due to the novelty of these compounds, the available data is limited and provides challenges to toxicologists. The focus of this project was to examine the postmortem distribution of new synthetic opioids in blood, vitreous humor, and brain tissue. New methods were developed and validated to quantify 13 synthetic opioids …

Macrophages But Not Astrocytes Harbor Hiv Dna In The Brains Of Hiv-1-Infected Aviremic Individuals On Suppressive Antiretroviral Therapy, Allen Ko, Guobin Kang, Julian B. Hattler, Hadiza I. Galadima, Junfeng Zhang, Qingsheng Li, Woong-Ki Kim

Community & Environmental Health Faculty Publications

The question of whether the human brain is an anatomical site of persistent HIV-1 infection during suppressive antiretroviral therapy (ART) is critical, but remains unanswered. The presence of virus in the brains of HIV patients whose viral load is effectively suppressed would demonstrate not only the potential for CNS to act as an anatomical HIV reservoir, but also the urgent need to understand the factors contributing to persistent HIV behind the blood-brain barrier. Here, we investigated for the first time the presence of cells harboring HIV DNA and RNA in the brains from subjects with undetectable plasma viral load and …

Minocycline Protects Developing Brain Against Ethanol-Induced Damage, Xin Wang, Kai Zhang, Fanmuyi Yang, Zhenhua Ren, Mei Xu, Jacqueline A. Frank, Zun-Ji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during the pregnancy and is the leading cause of mental retardation. Ethanol exposure during the development results in the loss of neurons in the developing brain, which may underlie many neurobehavioral deficits associated with FASD. It is important to understand the mechanisms underlying ethanol-induced neuronal loss and develop appropriate therapeutic strategies. One of the potential mechanisms involves neuroimmune activation. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that ethanol induced a wide-spread neuroapoptosis, microglial activation, and neuroinflammation in C57BL/6 mice. Minocycline is an antibiotic that inhibits …

Nonsurgical Approaches To Glioblastoma, Moshe Baitelman

The Science Journal of the Lander College of Arts and Sciences

Due to the sensitivity of location, brain cancer is one of the most difficult and deadly known cancers. There are various forms of cancer in the brain with many shared characteristics as well as unique manifestations in each. While cancers originating in the central nervous system present in several ways, the most common forms are high grade gliomas generally, and glioblastoma or anaplastic astrocytomas specifically. With the advent of technology, researchers have been able to propose and refine extensive profiles of these relentless tumors, enabling greater and more successful treatment profiles to be developed. Where treatments used to consist primarily …

Nfatc2 Modulates Microglial Activation In The Aβpp/Ps1 Mouse Model Of Alzheimer's Disease, Gunjan D. Manocha, Atreyi Ghatak, Kendra L. Puig, Susan D. Kraner, Christopher M. Norris, Colin K. Combs

Pharmacology and Nutritional Sciences Faculty Publications

Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or …

Calcium's Role As Nuanced Modulator Of Cellular Physiology In The Brain, Hilaree N. Frazier, Shaniya Maimaiti, Katie L. Anderson, Lawrence D. Brewer, John C. Gant, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can …

Translational Models For Vascular Cognitive Impairment: A Review Including Larger Species, Atticus H. Hainsworth, Stuart M. Allan, Johannes Boltze, Catriona Cunningham, Chad Farris, Elizabeth Head, Masafumi Ihara, Jeremy D. Isaacs, Raj N. Kalaria, Saskia A. M. J. Lesnik Oberstein, Mark B. Moss, Björn Nitzsche, Gary A. Rosenberg, Julie W. Rutten, Melita Salkovic-Petrisic, Aron M. Troen

Pharmacology and Nutritional Sciences Faculty Publications

Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited.

Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, …

Network-Driven Plasma Proteomics Expose Molecular Changes In The Alzheimer's Brain, Philipp A. Jaeger, Kurt M. Lucin, Markus Britschgi, Badri Vardarajan, Ruo-Pan Huang, Elizabeth D. Kirby, Rachelle Abbey, Bradley F. Boeve, Adam L. Boxer, Lindsay A. Farrer, Nicole Finch, Neill R. Graff-Radford, Elizabeth Head, Matan Hofree, Ruochun Huang, Hudson Johns, Anna Karydas, David S. Knopman, Andrey Loboda, Eliezer Masliah, Ramya Narasimhan, Ronald C. Petersen, Alexei Podtelezhnikov, Suraj Pradhan, Rosa Rademakers, Chung-Huan Sun, Steven G. Younkin, Bruce L. Miller, Trey Ideker, Tony Wyss-Coray

Pharmacology and Nutritional Sciences Faculty Publications

Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using …

An Investigation Of The Uptake, Distribution, And Accumulation Of Lead And Other Trace Elements In Caprine Brain Tissues Using Analytical Atomic Spectrometry, Amy Joanna Steuerwald

Legacy Theses & Dissertations (2009 - 2024)

Exposure to toxic elements and dysregulation of essential elements have been implicated in neurodegenerative disorders. Despite the importance of trace elements in neurological function, little is known regarding their uptake and distribution within brain tissues. Even less is known regarding the impact of toxic metal exposure (i.e., Pb) on endogenous metals within the brain.

Neuroinflammation And Neurologic Deficits In Diabetes Linked To Brain Accumulation Of Amylin, Sarah Srodulski, Savita Sharma, Adam B. Bachstetter, Jennifer M. Brelsfoard, Conrado Pascual, Xinmin Simon Xie, Kathryn E. Saatman, Linda J. Van Eldik, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

METHODS: In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. …

Role Of Erk1, 2, And 5 In Dopamine Neuron Survival During Aging, Mayur S. Parmar, Juliann D. Jaumotte, Stephanie L. Wyrostek, Michael J. Zigmond, Jane E. Cavanaugh

HPD Articles

Extracellular signal-regulated kinases (ERKs) 1, 2, and 5 have been shown to play distinct roles in proliferation, differentiation, and neuronal viability. In this study, we examined ERK1, 2, and 5 expression and activation in the substantia nigra (SN), striatum (STR), and ventral tegmental area (VTA) during aging. An age-related decrease in phosphorylated ERK5 was observed in the SN and STR, whereas an increase in total ERK1 was observed in all 3 regions. In primary cultures of the SN and VTA, inhibition of ERK5 but not ERK1 and 2 decreased dopamine neuronal viability significantly. These data suggest that ERK5 is essential …

Rat Brain Pro-Oxidant Effects Of Peripherally Administered 5 Nm Ceria 30 Days After Exposure, Sarita S. Hardas, Rukhsana Sultana, Govind Warrier, Mo Dan, Rebecca L. Florence, Peng Wu, Eric A. Grulke, Michael T. Tseng, Jason M. Unrine, Uschi M. Graham, Robert A. Yokel, D. Allan Butterfield

Chemistry Faculty Publications

The objective of this study was to determine the residual pro-or anti-oxidant effects in rat brain 30 days after systemic administration of a 5 nm citrate-stabilized ceria dispersion. A ∼4% aqueous ceria dispersion was iv-infused (0 or 85 mg/kg) into rats which were terminated 30 days later. Ceria concentration, localization, and chemical speciation in the brain was assessed by inductively coupled plasma mass spectrometry (ICP-MS), light and electron microscopy (EM), and electron energy loss spectroscopy (EELS), respectively. Pro- or anti-oxidant effects were evaluated by measuring levels of protein carbonyls (PC), 3-nitrotyrosine (3NT), and protein-bound-4-hydroxy-2-trans-nonenal (HNE) in the hippocampus, cortex, and …

Reversal Of Glial And Neurovascular Markers Of Unhealthy Brain Aging By Exercise In Middle-Aged Female Mice, Caitlin S. Latimer, James L. Searcy, Michael T. Bridges, Lawrence D. Brewer, Jelena Popović, Eric M. Blalock, Philip W. Landfield, Olivier Thibault, Nada M. Porter

Pharmacology and Nutritional Sciences Faculty Publications

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for …

Effects Of Long-Term Pioglitazone Treatment On Peripheral And Central Markers Of Aging, Eric M. Blalock, Jeremiah T. Phelps, Tristano Pancani, James L. Searcy, Katie L. Anderson, John C. Gant, Jelena Popovic, Margarita G. Avdiushko, Don A. Cohen, Kuey-Chu Chen, Nada M. Porter, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer's disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While TZD's actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and …

Antidepressant Stimulation Of Cdp-Diacylglycerol Synthesis Does Not Require Monoamine Reuptake Inhibition, Ashiwel S. Undieh, Marwa A. Aboukhatwa

Publications and Research

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of …

Expansion Of The Calcium Hypothesis Of Brain Aging And Alzheimer's Disease: Minding The Store, Olivier Thibault, John C. Gant, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca2+ hypothesis of brain aging and dementia. Electrophysiological, imaging, and behavioral studies in hippocampal or cortical neurons of rodents and rabbits have revealed aging-related increases in the slow afterhyperpolarization, Ca2+ spikes and currents, Ca2+transients, and L-type voltage-gated Ca2+ channel (L-VGCC) activity. Several of these changes have been associated with age-related deficits in learning or memory. Consequently, one version of the Ca2+ hypothesis has been that increased L-VGCC activity drives many of the other Ca2+-related biomarkers of hippocampal aging. …

Manganese Distribution Across The Blood-Brain Barrier. Iv. Evidence For Brain Influx Through Store-Operated Calcium Channels, Janelle S. Crossgrove, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is a required co-factor for many ubiquitous enzymes; however, chronic Mn overexposure can cause manganism, a parkinsonian-like syndrome. Previous studies showed Mn influx into brain is carrier-mediated, though the putative carrier(s) were not established. Studies conducted with cultured bovine brain microvascular endothelial cells (bBMECs), which comprise the blood–brain barrier, revealed ⁵⁴Mn (II) uptake positively correlated with pH, was temperature-dependent, and was sodium- and energy-independent. Brain ⁵⁴Mn uptake correlated inversely with calcium (Ca) concentration, but ⁴⁵Ca uptake was unaltered by high Mn concentration. Lanthanum (La), a non-selective inhibitor of several Ca channel types, as well as …

Manganese Distribution Across The Blood-Brain Barrier. I. Evidence For Carrier-Mediated Influx Of Managanese Citrate As Well As Manganese And Manganese Transferrin, Janelle S. Crossgrove, David D. Allen, Bonny L. Bukaveckas, Susan S. Rhineheimer, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is an essential element and a neurotoxicant. Regulation of Mn movement across the blood–brain barrier (BBB) contributes to whether the brain Mn concentration is functional or toxic. In plasma, Mn associates with water, small molecular weight ligands and proteins. Mn speciation may influence the kinetics of its movement through the BBB. In the present work, the brain influx rates of ⁵⁴Mn²⁺, ⁵⁴Mn citrate and ⁵⁴Mn transferrin (⁵⁴Mn Tf) were determined using the in situ brain perfusion technique. The influx rates were compared to their predicted diffusion rates, which were determined from …

The Toxicology Of Aluminum In The Brain: A Review, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Aluminum is environmentally ubiquitous, providing human exposure. Usual human exposure is primarily dietary. The potential for significant Al absorption from the nasal cavity and direct distribution into the brain should be further investigated. Decreased renal function increases human risk of Al-induced accumulation and toxicity. Brain Al entry from blood may involve transferrin-receptor mediated endocytosis and a more rapid process transporting small molecular weight Al species. There appears to be Al efflux from the brain, probably as Al citrate. There is prolonged retention of a fraction of Al that enters the brain, suggesting the potential for accumulation with repeated exposure. Al …

Influence Of 2,5-Hexanedione, Acrylamide, Tri-O-Tolyl Phosphate, Leptophos And Methylmercury On Endogenous Levels Of Tryptophan, Serotonin And 5-Hydroxyindoleacetic Acid And Serotonin Turnover Rates In Rat Brain, Craig H. Farr

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

Several industrial and environmental chemicals cause distal and/or central neuropathy among other diverse toxic effects. Spague-Dawley derived rats were fed doses of 2,5-hexanedione, acrylamide, tri-o-tolyl phosphate, Leptophos and methylmercury via gavage. The dose levels and administration periods were established in previous experiments designed to assess clinical neuropathy using rats trained to walk on a rotorod apparatus fitted with an electrode floor. After intravenous injections of ³H-Tryptophan, whole rat brain homogenates were analyzed using liquid scintillation and spectrofluorometric techniques for levels of tryptophan, serotonin and 5-hydroxyindoleacetic acid. Serotonin turnover rates were calculated using the specific activities of tryptophan and serotonin …

Alterations In Rat Brain Norepinephrine And Dopamine Levels And Synthesis Rates In Response To Five Neurotoxic Chemicals: Acrylamide, 2,5-Hexanedione, Tri-O-Tolyl Phosphate, Leptophos, And Methyl Mercuric Chloride, Charles N. Aldous

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

Acrylamide, 2,5-hexanedione, Tri-o-tolyl phosphate and leptophos belong to three fundamentally different chemical classes but all four chemicals cause central-peripheral distal axonopathy. Some of these compounds have been shown to alter brain steady state levels of neurotransmitters or to inhibit the activities of adenosine triphosphatases which are involved in the uptake and storage of biogenic amines. Tests were performed to determine alterations in steady state levels of rat brain norepinephrine and dopamine in response to doses of the above chemicals and of the central nervous system toxin, methyl mercuric chloride sufficient to cause ataxia. Catecholamine synthesis rate constant estimations were performed. …