Medicine and Health Sciences Commons^™

Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive And Electrophysiological Impairments In Tg2576 App Transgenic Mice, Madhumathi Gnanaprakash, Agnieszka Staniszewski, Hong Zhang, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ).

Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. …

Supplemental Ascorbate Diminishes Dna Damage Yet Depletes Glutathione And Increases Acute Liver Failure In A Mouse Model Of Hepatic Antioxidant System Disruption, Colin G. Miller, Jean A. Kundert, Justin R. Prigge, Julie A. Amato, Allison E. Perez, Lucia Coppo, Gabrielle N. Rizzo, Michael P. Kavanaugh, David J. Orlicky, Colin T. Shearn, Edward E. Schmidt

Biomedical and Pharmaceutical Sciences Faculty Publications

Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific codisruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate …

Prion Protein Lowering Is A Disease-Modifying Therapy Across Prion Disease Stages, Strains And Endpoints, Eric Vallabh Minikel, Hien T. Zhao, Jason Le, Jill O'Moore, Rose Pitstick, Samantha Graffam, George A. Carlson, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

Reduced Expression Of The Pp2a Methylesterase, Pme-1, Or The Pp2a Methyltransferase, Lcmt-1, Alters Sensitivity To Beta-Amyloid-Induced Cognitive And Electrophysiological Impairments In Mice, Agnieszka Staniszewski, Hong Zhang, Kesava Asam, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Biomedical and Pharmaceutical Sciences Faculty Publications

Beta-amyloid (Ab) is thought to play a critical role in Alzheimer’s disease (AD), and application of soluble oligomeric forms of Ab produces AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic overexpression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to Ab-induced impairments, suggesting that PME-1 inhibition may be an effective approach for preventing or treating these impairments. To explore this possibility, we examined the behavioral and electrophysiological effects of acutely applied synthetic Ab oligomers in male and female mice heterozygous for either a PME-1 KO or …

Modeling Of Excitatory Amino Acid Transporters And Clearance Of Synaptic Cleft On Millisecond Time Scale, Denis M. Shchepakin, Leonid Kalachev, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Excitatory Amino Acid Transporters (EAATs) operate over wide time scales in the brain. They maintain low ambient concentrations of the primary excitatory amino acid neurotransmitter glutamate, but they also seem to play a significant role in clearing glutamate from the synaptic cleft in the millisecond time-scale process of chemical communication that occurs between neurons. The detailed kinetic mechanisms underlying glutamate uptake and clearance remain incompletely understood. In this work we used a combination of methods to model EAAT kinetics and gain insight into the impact of transport on glutamate dynamics in a general sense. We derive reliable estimates of the …

D-Serine Is A Substrate For Neutral Amino Acid Transporters Asct1/Slc1a4 And Asct2/Slc1a5, And Is Transported By Both Subtypes In Rat Hippocampal Astrocyte Cultures, Alan C. Foster, Jill Farnsworth, Genevieve Lind, Yong-Xin Lin, Jia-Ying Yang, Van Dang, Mahmud Penjwini, Veena Viswanath, Ursula Staubli, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

N-methyl-D-aspartate (NMDA) receptors play critical roles in synaptic transmission and plasticity. Activation of NMDA receptors by synaptically released L-glutamate also requires occupancy of co-agonist binding sites in the tetrameric receptor by either glycine or D-serine. Although D-serine appears to be the predominant co-agonist at synaptic NMDA receptors, the transport mechanisms involved in D-serine homeostasis in brain are poorly understood. In this work we show that the SLC1 amino acid transporter family members SLC1A4 (ASCT1) and SLC1A5 (ASCT2) mediate homo- and hetero-exchange of D-serine with physiologically relevant kinetic parameters. In addition, the selectivity profile of D-serine uptake in cultured rat hippocampal …

Modeling Of Ambient Glutamate Concentration Measurement In The Mammalian Nervous System, Denis M. Shchepakin, Michael Kavanaugh, Leonid Kalachev

Biomedical and Pharmaceutical Sciences Faculty Publications

A neuron is an electrically excitable cell that processes and transmits information through electrical and chemical signals. Neurons connect and pass signals to other cells through the structure called synapse. We focus on synapses through which the signals are transferred by signaling molecules called neurotransmitters. One of the predominant excitatory neurotransmitters in the central nervous system of the mammals, including humans, is glutamate. It is directly or indirectly involved in most brain functions. However, the excessive stimulation of the glutamate receptors is toxic to neurons, therefore it is important to rapidly clear the glutamate from the extra-cellular space and keep …

Temporal And Spatial Changes In The Pattern Of Iba1 And Cd68 Staining In The Rat Brain Following Severe Traumatic Brain Injury, Debbie Smith, Diane Brooks, Eric Wohlgehagen, Thomas Rau, David Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

We have previously demonstrated that acute treatment with low dose methamphetamine is neuroprotectivein a rat model of severe traumatic brain injury (TBI). Using gene expression analysis, we further showed that methamphetamine treatment significantly reduced the expression of proinflammatory genes after severe TBI. Therefore, to further investigate the potential effects of methamphetamine treatment on the neuroinflammatory response, we examined immunofluorescent staining of Iba1 and CD68, two marker of neuroinflammation, in the rat lateral fluid percussion injury model of severe TBI. In this study, we observed temporal and spatial alterations in the pattern of Iba1 and CD68 labeling within two weeks after …

Dendritic Distributions Of LH Channels In Experimentally-Derived Multi-Compartment Models Of Oriens-Lacunosum/Moleculare (O-Lm) Hippocampal Interneurons, Vladislav Sekulic, Tse-Chiang Chen, J. Josh Lawrence, Frances K. Skinner

Biomedical and Pharmaceutical Sciences Faculty Publications

The O-LM cell type mediates feedback inhibition onto hippocampal pyramidal cells and gates information flow in the CA1. Its functions depend on the presence of voltage-gated channels (VGCs), which affect its integrative properties and response to synaptic input. Given the challenges associated with determining densities and distributions of VGCs on interneuron dendrites, we take advantage of computational modeling to consider different possibilities. In this work, we focus on hyperpolarization-activated channels (h-channels) in O-LM cells. While h-channels are known to be present in O-LM cells, it is unknown whether they are present on their dendrites. In previous work, we used ensemble …

Using Multi-Compartment Ensemble Modeling As An Investigative Tool Of Spatially Distributed Biophysical Balances: Application To Hippocampal Oriens-Lacunosum/Moleculare (O-Lm) Cellns, Vladislav Sekulic, J. Josh Lawrence, Frances K. Skinner

Biomedical and Pharmaceutical Sciences Faculty Publications

Multi-compartmental models of neurons provide insight into the complex, integrative properties of dendrites. Because it is not feasible to experimentally determine the exact density and kinetics of each channel type in every neuronal compartment, an essential goal in developing models is to help characterize these properties. To address biological variability inherent in a given neuronal type, there has been a shift away from using hand-tuned models towards using ensembles or populations of models. In collectively capturing a neuron’s output, ensemble modeling approaches uncover important conductance balances that control neuronal dynamics. However, conductances are never entirely known for a given neuron …

Synthesis, Characterization, And Bioactivity Of Carboxylic Acid-Functionalized Titanium Dioxide Nanobelts, Raymond F. Hamilton, Nianqiang Wu, Chengcheng Xiang, Ming Li, Feng Yang, Michael Wolfarth, Dale W. Porter, Andrij Holian

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Surface modification strategies to reduce engineered nanomaterial (ENM) bioactivity have been used successfully in carbon nanotubes. This study examined the toxicity and inflammatory potential for two surface modifications (humic acid and carboxylation) on titanium nanobelts (TNB).

Methods: The in vitro exposure models include C57BL/6 alveolar macrophages (AM) and transformed human THP-1 cells exposed to TNB for 24 hrs in culture. Cell death and NLRP3 inflammasome activation (IL-1β release) were monitored. Short term (4 and 24 hr) in vivo studies in C57BL/6, BALB/c and IL-1R null mice evaluated inflammation and cytokine release, and cytokine release from ex vivo cultured AM. …

Household Reporting Of Childhood Respiratory Health And Air Pollution In Rural Alaska Native Communities, Desirae N. Ware, Johnnye Lewis, Scarlett Hopkins, Bert Boyer, Luke Montrose, Curis W. Noonan, Erin O. Semmens, Tony J. Ward

Biomedical and Pharmaceutical Sciences Faculty Publications

Background. Air pollution is an important contributor to respiratory disease in children.

Objective. To examine associations between household reporting of childhood respiratory conditions and household characteristics related to air pollution in Alaska Native communities.

Design. In-home surveys were administered in 2 rural regions of Alaska. The 12-month prevalence of respiratory conditions was summarized by region and age. Odds ratios (ORs) were calculated to describe associations between respiratory health and household and air quality characteristics.

Results. Household-reported respiratory health data were collected for 561 children in 328 households. In 1 region, 33.6% of children aged/or bronchitis. Children with these conditions …

The Effect Of Size On Ag Nanosphere Toxicity In Macrophage Cell Models And Lung Epithelial Cell Lines Is Dependent On Particle Dissolution, Raymond F. Hamilton, Sarah Buckingham, Andrij Holian

Biomedical and Pharmaceutical Sciences Faculty Publications

Silver (Ag) nanomaterials are increasingly used in a variety of commercial applications. This study examined the effect of size (20 and 110 nm) and surface stabilization (citrate and PVP coatings) on toxicity, particle uptake and NLRP3 inflammasome activation in a variety of macrophage and epithelial cell lines. The results indicated that smaller Ag (20 nm), regardless of coating, were more toxic in both cell types and most active in the THP-1 macrophages. TEM imaging demonstrated that 20 nm Ag nanospheres dissolved more rapidly than 110 nm Ag nanospheres in acidic phagolysosomes consistent with Ag ion mediated toxicity. In addition, there …

Glutamate Transporter Control Of Ambient Glutamate Levels, Weinan Sun, Denis M. Shchepakin, Leonid Kalachev, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Accurate knowledge of the ambient extracellular glutamate concentration in brain is required for understanding its potential impacts on tonic and phasic receptor signaling. Estimates of ambient glutamate based on microdialysis measurements are generally in the range of ∼2–10 μM, approximately 100-fold higher than estimates based on electrophysiological measurements of tonic NMDA receptor activity (∼25–90 nM). The latter estimates are closer to the low nanomolar estimated thermodynamic limit of glutamate transporters. The reasons for this discrepancy are not known, but it has been suggested that microdialysis measurements could overestimate ambient extracellular glutamate because of reduced glutamate transporter activity in a …

Hilar Mossy Cells Provide The First Glutamatergic Synapses To Adult-Born Dentate Granule Cells, Jessica H. Chancey, David J. Poulsen, Jacques I. Wadiche, Linda Overstreet-Wadiche

Biomedical and Pharmaceutical Sciences Faculty Publications

Adult-generated granule cells (GCs) in the dentate gyrus must establish synapses with preexisting neurons to participate in network activity. To determine the source of early glutamatergic synapses on newborn GCs in adult mice, we examined synaptic currents at the developmental stage when NMDA receptor-mediated silent synapses are first established. We show that hilar mossy cells provide initial glutamatergic synapses as well as disynaptic GABAergic input to adult-generated dentate GCs.

Phenoxybenzamine Is Neuroprotective In A Rat Model Of Severe Traumatic Brain Injury, Thomas Rau, Aakriti Kothiwal, Annela Rova, Joseph F. Rhoderick, David J. Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 μM–1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered …

Analgesic Effect Of A Mixed T-Type Channel Inhibitor/Cb2 Receptor Agonist, Vinicius M. Gadotti, Haitao You, Ravil R. Petrov, N. Daniel Berger, Philippe Diaz, Gerald W. Zamponi

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. Results: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTP gamma[S-35] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Ca(V)3.2 currents with IC50 values …

Mri Of Neuronal Recovery After Low-Dose Methamphetamine Treatment Of Traumatic Brain Injury In Rats, Guang Liang Ding, Michael Chopp, David J. Poulsen, Lian Li, Changsheng Qu, Qingjiang Li, Siamak P. Nejad-Davarani, John S. Budaj, Hongtao Wu, Asim Mahmood, Quan Jiang

Biomedical and Pharmaceutical Sciences Faculty Publications

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day …

Exposure To Urban Air Pollution And Bone Health In Clinically Healthy Six-Year-Old Children, Lilian Calderón-Garcidueñas, Antonieta Mora-Tiscareño, Maricela Franco-Lira, Ricardo Torres-Jardon, Bernardo Pena-Cruz, Carolina Palacios-López, Hongtu Zhu, Linglong Kong, Nicolas Mendoza-Mendoza, Hortencia Montesinoscorrea, Lina Romero, Gildardo Valencia-Salazar, Michael Kavanaugh, Silvestre Frenk

Biomedical and Pharmaceutical Sciences Faculty Publications

Air pollution induces systemic inflammation, as well as respiratory, myocardial and brain inflammation in children. Peak bone mass is influenced by environmental factors. We tested the hypothesis that six-year-olds with lifetime exposures to urban air pollution will have alterations in inflammatory markers and bone mineral density (BMD) as opposed to low-polluted city residents when matched for BMI, breast feeding history, skin phototype, age, sex and socioeconomic status. This pilot study included 20 children from Mexico City (MC) (6.17 years ± 0.63 years) and 15 controls (6.27 years ± 0.76 years). We performed full paediatric examinations, a history of outdoor exposures, …

Brain Immune Interactions And Air Pollution: Macrophage Inhibitory Factor (Mif), Prion Cellular Protein (Prpc), Interleukin-6 (Il-6), Interleukin 1 Receptor Antagonist (Il-1ra), And Interleukin-2 (Il-2) In Cerebrospinal Fluid And Mif In Serum Differentiate Urban Children Exposed To Severe Vs. Low Air Pollution, Lilian Calderón-Garcidueñas, Janet V. Cross, Maricela Franco-Lira, Mariana Aragón-Flores, Michael Kavanaugh, Ricardo Torres-Jardon, Chih-Kai Chao, Charles Thompson, Jing Chang, Hongtu Zhu, Amedeo D'Angiulli

Biomedical and Pharmaceutical Sciences Faculty Publications

Mexico City Metropolitan Area children chronically exposed to high concentrations of air pollutants exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses along with accumulation of misfolded proteins observed in the early stages of Alzheimer and Parkinson's diseases. A complex modulation of serum cytokines and chemokines influences children's brain structural and gray/white matter volumetric responses to air pollution. The search for biomarkers associating systemic and CNS inflammation to brain growth and cognitive deficits in the short term and neurodegeneration in the long-term is our principal aim. We explored and compared a profile …

Novel Dicarboxylate Selectivity In An Insect Glutamate Transporter Homolog, Hui Wang, Avi M. Rascoe, David Charles Holley, Eric Gouaux, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Mammals express seven transporters from the SLC1 (solute carrier 1) gene family, including five acidic amino acid transporters (EAAT1-5) and two neutral amino acid transporters (ASCT1-2). In contrast, insects of the order Diptera possess only two SLC1 genes. In this work we show that in the mosquito Culex quinquefasciatus, a carrier of West Nile virus, one of its two SLC1 EAAT-like genes encodes a transporter that displays an unusual selectivity for dicarboxylic acids over acidic amino acids. In eukaryotes, dicarboxylic acid uptake has been previously thought to be mediated exclusively by transporters outside the SLC1 family. The dicarboxylate selectivity was …

Early Alzheimer's And Parkinson's Disease Pathology In Urban Children: Friend Versus Foe Responses—It Is Time To Face The Evidence, Lilian Calderón-Garcidueñas, Maricela Franco-Lira, Antonieta Mora-Tiscareño, Humberto Medina-Cortina, Ricardo Torres-Jardon, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascularrelated sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPrc), alpha-synuclein, and beta-amyloid could …

Oxygen Glucose Deprivation In Rat Hippocampal Slice Cultures Results In Alterations In Carnitine Homeostasis And Mitochondrial Dysfunction, Thomas Rau, Qing Lu, Shruti Sharma, Xutong Sun, Gregory Leary, Matthew L. Beckman, Yal Hou, Mark S. Wainwright, Michael P. Kavanaugh, David J. Poulsen, Stephen M. Black

Biomedical and Pharmaceutical Sciences Faculty Publications

Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we …

Identifying Neurotransmitter Spill-Over In Hippocampal Field Recordings, Emily Stone, Katie Hoffman, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

A model of synaptic and extra-synaptic excitatory signaling in the hippocampus is presented. The model is used to analytically evaluate the potential contributions of homosynaptic and heterosynaptic glutamate spill-over to receptor signaling during an electrophysiological experiment in which glutamate transporters are pharmacologically blocked. Inhibition of glutamate uptake selectively prolongs the decay kinetics of the second field excitatory postsynaptic potential evoked by paired pulse stimulation of Schaffer collateral axons in area CA1. The model includes AMPA and NMDA glutamate receptors, and the removal of glutamate by transporters and diffusion. We establish analytically that the prolongation cannot be caused by local …

Single Mutation To A Sex Pheromone Receptor Provides Adaptive Specificity Between Closely Related Moth Species, Gregory Patrick Leary, Jean E. Allen, Peggy L. Bunger, Jena B. Luginbill, Charles E. Linn Jr., Irene E. Macallister, Michael Kavanaugh, Kevin W. Wanner

Biomedical and Pharmaceutical Sciences Faculty Publications

Sex pheromone communication, acting as a prezygotic barrier to mating, is believed to have contributed to the speciation of moths and butterflies in the order Lepidoptera. Five decades after the discovery of the first moth sex pheromone, little is known about the molecular mechanisms that underlie the evolution of pheromone communication between closely related species. Although Asian and European corn borers (ACB and ECB) can be interbred in the laboratory, they are behaviorally isolated from mating naturally by their responses to subtly different sex pheromone isomers, (E)-12- and (Z)-12-tetradecenyl acetate and (E)-11- and (Z)-11-tetradecenyl acetate (ACB: E12, Z12; ECB; E11, …

Functional Characterization And Analgesic Effects Of Mixed Cannabinoid Receptor/T-Type Channel Ligands, Haitao You, Vinicius M. Gadotti, Ravil R. Petrov, Gerald W. Zamponi, Philippe Diaz

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity. Results: Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. …

Specificity And Actions Of An Arylaspartate Inhibitor Of Glutamate Transport At The Schaffer Collateral-Ca1 Pyramidal Cell Synapse, Weinan Sun, Katie M. Hoffman, David C. Holley, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-beta-benzylaspartate (L-TBA). At concentrations up to 100 mu M, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg(2+) concentrations, but in Mg(2+)-free solution, EPSCs …

Specificity And Actions Of An Arylaspartate Inhibitor Of Glutamate Transport At The Schaffer Collateral-Ca1 Pyramidal Cell Synapse, Weinan Sun, Katie Hoffman, David C. Holley, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-ß-benzylaspartate (L-TBA). At concentrations up to 100 µM, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg2+ concentrations, but in Mg2+-free solution, EPSCs were …

From Good Intentions To Proven Interventions: Effectiveness Of Actions To Reduce The Health Impacts Of Air Pollution, Luisa V. Giles, Prabjit Barn, Nino Kuenzli, Isabelle Romieu, Murray A. Mittleman, Stephan Van Eeden, Ryan Allen, Chris Carlsten, Dave Stieb, Curtis W. Noonan, Audrey Smargiassi, Joel D. Kaufman, Shakoor Hajat, Tom Kosatsky, Michael Brauer

Biomedical and Pharmaceutical Sciences Faculty Publications

BACKGROUND: Associations between air pollution and a multitude of health effects are now well established. Given ubiquitous exposure to some level of air pollution, the attributable health burden can be high, particularly for susceptible populations. OBJECTIVES: An international multidisciplinary workshop was convened to discuss evidence of the effectiveness of actions to reduce health impacts of air pollution at both the community and individual level. The overall aim was to summarize current knowledge regarding air pollution exposure and health impacts leading to public health recommendations. DISCUSSION: During the workshop, experts reviewed the biological mechanisms of action of air pollution in the …

The Central Cavity In Trimeric Glutamate Transporters Restricts Ligand Diffusion, Gregory Patrick Leary, David Charles Holley, Emily F. Stone, Brent Russell Lyda, Leonid Kalachev, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

A prominent aqueous cavity is formed by the junction of three identical subunits in the excitatory amino acid transporter (EAAT) family. To investigate the effect of this structure on the interaction of ligands with the transporter, we recorded currents in voltage-clamped Xenopus oocytes expressing EAATs and used concentration jumps to measure binding and unbinding rates of a high-affinity aspartate analog that competitively blocks transport (β-2-fluorenyl-aspartylamide; 2-FAA). The binding rates of the blocker were approximately one order of magnitude slower than l-Glu and were not significantly different for EAAT1, EAAT2, or EAAT3, but 2-FAA exhibited higher affinity for the neuronal transporter …