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Isoflurane and ketamine:xylazine differentially affect intraocular pressure-associated scotopic threshold responses in Sprague-Dawley rats.
Choh V, Gurdita A, Tan B, Feng Y, Bizheva K, McCulloch DL, Joos KM
(2017) Doc Ophthalmol 135: 121-132
MeSH Terms: Anesthetics, Combined, Anesthetics, Inhalation, Animals, Dark Adaptation, Electroretinography, Injections, Intraperitoneal, Intraocular Pressure, Isoflurane, Ketamine, Male, Night Vision, Rats, Rats, Sprague-Dawley, Retina, Sensory Thresholds, Xylazine
Show Abstract · Added March 19, 2018
PURPOSE - Amplitudes of electroretinograms (ERG) are enhanced during acute, moderate elevation of intraocular pressure (IOP) in rats anaesthetised with isoflurane. As anaesthetics alone are known to affect ERG amplitudes, the present study compares the effects of inhalant isoflurane and injected ketamine:xylazine on the scotopic threshold response (STR) in rats with moderate IOP elevation.
METHODS - Isoflurane-anaesthetised (n = 9) and ketamine:xylazine-anaesthetised (n = 6) rats underwent acute unilateral IOP elevation using a vascular loop anterior to the equator of the right eye. STRs to a luminance series (subthreshold to -3.04 log scotopic cd s/m) were recorded from each eye of Sprague-Dawley rats before, during, and after IOP elevation.
RESULTS - Positive STR (pSTR) amplitudes for all conditions were significantly smaller (p = 0.0001) for isoflurane- than for ketamine:xylazine-anaesthetised rats. In addition, ketamine:xylazine was associated with a progressive increase in pSTR amplitudes over time (p = 0.0028). IOP elevation was associated with an increase in pSTR amplitude (both anaesthetics p < 0.0001). The absolute interocular differences in IOP-associated enhancement of pSTR amplitudes for ketamine:xylazine and isoflurane were similar (66.3 ± 35.5 vs. 54.2 ± 24.1 µV, respectively). However, the fold increase in amplitude during IOP elevation was significantly higher in the isoflurane- than in the ketamine:xylazine-anaesthetised rats (16.8 ± 29.7x vs. 2.1 ± 2.7x, respectively, p = 0.0004).
CONCLUSIONS - The anaesthetics differentially affect the STRs in the rat model with markedly reduced amplitudes with isoflurane compared to ketamine:xylazine. However, the IOP-associated enhancement is of similar absolute magnitude for the two anaesthetics, suggesting that IOP stress and anaesthetic effects operate on separate retinal mechanisms.
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16 MeSH Terms
Improved proliferation of antigen-specific cytolytic T lymphocytes using a multimodal nanovaccine.
Li B, Siuta M, Bright V, Koktysh D, Matlock BK, Dumas ME, Zhu M, Holt A, Stec D, Deng S, Savage PB, Joyce S, Pham W
(2016) Int J Nanomedicine 11: 6103-6121
MeSH Terms: Adjuvants, Immunologic, Administration, Intranasal, Animals, Cell Death, Cell Proliferation, Dendritic Cells, Galactosylceramides, Immunization, Injections, Intraperitoneal, Lactic Acid, Mice, Mice, Inbred C57BL, Microscopy, Atomic Force, Nanoparticles, Ovalbumin, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, T-Lymphocytes, Vaccines
Show Abstract · Added March 21, 2018
The present study investigated the immunoenhancing property of our newly designed nanovaccine, that is, its ability to induce antigen-specific immunity. This study also evaluated the synergistic effect of a novel compound PBS-44, an α-galactosylceramide analog, in boosting the immune response induced by our nanovaccine. The nanovaccine was prepared by encapsulating ovalbumin (ova) and an adjuvant within the poly(lactic-co-glycolic acid) nanoparticles. Quantitative analysis of our study data showed that the encapsulated vaccine was physically and biologically stable; the core content of our nanovaccine was found to be released steadily and slowly, and nearly 90% of the core content was slowly released over the course of 25 days. The in vivo immunization studies exhibited that the nanovaccine induced stronger and longer immune responses compared to its soluble counterpart. Similarly, intranasal inhalation of the nanovaccine induced more robust antigen-specific CD8 T cell response than intraperitoneal injection of nanovaccine.
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19 MeSH Terms
Mu-opioid receptor inhibition decreases voluntary wheel running in a dopamine-dependent manner in rats bred for high voluntary running.
Ruegsegger GN, Brown JD, Kovarik MC, Miller DK, Booth FW
(2016) Neuroscience 339: 525-537
MeSH Terms: Animals, Cells, Cultured, Dopamine, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Feeding Behavior, Female, Injections, Intraperitoneal, Motivation, Motor Activity, Naltrexone, Narcotic Antagonists, Neurons, Nucleus Accumbens, Oxidopamine, RNA, Messenger, Rats, Receptors, Opioid, mu, Running, Sedentary Behavior, Species Specificity, Volition
Show Abstract · Added October 23, 2017
The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake.
Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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21 MeSH Terms
Erythropoietin either Prevents or Exacerbates Retinal Damage from Eye Trauma Depending on Treatment Timing.
Bricker-Anthony C, D'Surney L, Lunn B, Hines-Beard J, Jo M, Bernardo-Colon A, Rex TS
(2017) Optom Vis Sci 94: 20-32
MeSH Terms: Animals, Blast Injuries, Cell Survival, Dependovirus, Disease Models, Animal, Erythropoietin, Eye Injuries, Ferritins, Genetic Therapy, Genetic Vectors, Green Fluorescent Proteins, In Situ Nick-End Labeling, Injections, Intramuscular, Injections, Intraperitoneal, Mice, Mice, Inbred BALB C, Mice, Inbred DBA, NADPH Oxidases, Oxidative Stress, Polymerase Chain Reaction, Retina, Retinal Diseases, Time Factors, Vision Disorders, Wounds, Nonpenetrating
Show Abstract · Added April 2, 2019
PURPOSE - Erythropoietin (EPO) is a promising neuroprotective agent and is currently in Phase III clinical trials for the treatment of traumatic brain injury. The goal of this study was to determine if EPO is also protective in traumatic eye injury.
METHODS - The left eyes of anesthetized DBA/2J or Balb/c mice were exposed to a single 26 psi overpressure air-wave while the rest of the body was shielded. DBA/2J mice were given intraperitoneal injections of EPO or buffer and analyses were performed at 3 or 7 days post-blast. Balb/c mice were given intramuscular injections of rAAV.EpoR76E or rAAV.eGFP either pre- or post-blast and analyses were performed at 1 month post-blast.
RESULTS - EPO had a bimodal effect on cell death, glial reactivity, and oxidative stress. All measures were increased at 3 days post-blast and decreased at 7-days post-blast. Increased retinal ferritin and NADPH oxygenases were detected in retinas from EPO-treated mice. The gene therapy approach protected against axon degeneration, cell death, and oxidative stress when given after blast, but not before.
CONCLUSIONS - Systemic, exogenous EPO and EPO-R76E protects the retina after trauma even when initiation of treatment is delayed by up to 3 weeks. Systemic treatment with EPO or EPO-R76E beginning before or soon after trauma may exacerbate protective effects of EPO within the retina as a result of increased iron levels from erythropoiesis and, thus, increased oxidative stress within the retina. This is likely overcome with time as a result of an increase in levels of antioxidant enzymes. Either intraocular delivery of EPO or treatment with non-erythropoietic forms of EPO may be more efficacious.
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Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer.
Uddin MJ, Werfel TA, Crews BC, Gupta MK, Kavanaugh TE, Kingsley PJ, Boyd K, Marnett LJ, Duvall CL
(2016) Biomaterials 92: 71-80
MeSH Terms: Animals, Cell Line, Tumor, Cyclooxygenase 2, Dynamic Light Scattering, Female, Humans, Indoles, Inflammation, Injections, Intraperitoneal, Mice, Inbred C57BL, Mice, Nude, Molecular Imaging, Nanoparticles, Neoplasms, Polymers, Rhodamines, Tissue Distribution
Show Abstract · Added March 14, 2018
Cyclooxygenase-2 (COX-2) is expressed in virtually all solid tumors and its overexpression is a hallmark of inflammation. Thus, it is a potentially powerful biomarker for the early clinical detection of inflammatory disease and human cancers. We report a reactive oxygen species (ROS) responsive micellar nanoparticle, PPS-b-POEGA, that solubilizes the first fluorescent COX-2-selective inhibitor fluorocoxib A (FA) for COX-2 visualization in vivo. Pharmacokinetics and biodistribution of FA-PPS-b-POEGA nanoparticles (FA-NPs) were assessed after a fully-aqueous intravenous (i.v.) administration in wild-type mice and revealed 4-8 h post-injection as an optimal fluorescent imaging window. Carrageenan-induced inflammation in the rat and mouse footpads and 1483 HNSCC tumor xenografts were successfully visualized by FA-NPs with fluorescence up to 10-fold higher than that of normal tissues. The targeted binding of the FA cargo was blocked by pretreatment with the COX-2 inhibitor indomethacin, confirming COX-2-specific binding and local retention of FA at pathological sites. Our collective data indicate that FA-NPs are the first i.v.-ready FA formulation, provide high signal-to-noise in inflamed, premalignant, and malignant tissues, and will uniquely enable clinical translation of the poorly water-soluble FA compound.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin.
Begg DP, May AA, Mul JD, Liu M, D'Alessio DA, Seeley RJ, Woods SC
(2015) Diabetes 64: 2457-66
MeSH Terms: Animals, Appetite Depressants, Biological Transport, Body Composition, Body Weight, Brain, Eating, Hypoglycemic Agents, Injections, Intraperitoneal, Insulin, Insulin Detemir, Insulin, Isophane, Insulin, Long-Acting, Male, Mice, Mice, Inbred C57BL, Rats, Rats, Wistar
Show Abstract · Added March 2, 2017
Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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18 MeSH Terms
ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice.
Kaufmann K, Romaine I, Days E, Pascual C, Malik A, Yang L, Zou B, Du Y, Sliwoski G, Morrison RD, Denton J, Niswender CM, Daniels JS, Sulikowski GA, Xie XS, Lindsley CW, Weaver CD
(2013) ACS Chem Neurosci 4: 1278-86
MeSH Terms: Animals, Anticonvulsants, Calcium Signaling, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Electroshock, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, High-Throughput Screening Assays, Humans, Injections, Intraperitoneal, Mice, Microsomes, Liver, Molecular Structure, Patch-Clamp Techniques, Pentylenetetrazole, Phenylurea Compounds, Pyrazoles, Rats, Receptors, Metabotropic Glutamate, Recombinant Proteins, Seizures, Valproic Acid
Show Abstract · Added February 16, 2015
The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.
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23 MeSH Terms
Discovery of 2-(2-benzoxazoyl amino)-4-aryl-5-cyanopyrimidine as negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu₅): from an artificial neural network virtual screen to an in vivo tool compound.
Mueller R, Dawson ES, Meiler J, Rodriguez AL, Chauder BA, Bates BS, Felts AS, Lamb JP, Menon UN, Jadhav SB, Kane AS, Jones CK, Gregory KJ, Niswender CM, Conn PJ, Olsen CM, Winder DG, Emmitte KA, Lindsley CW
(2012) ChemMedChem 7: 406-14
MeSH Terms: Allosteric Regulation, Animals, Anxiety Disorders, Behavior, Animal, Benzoxazoles, Brain, Drug Discovery, Glutamic Acid, HEK293 Cells, High-Throughput Screening Assays, Humans, Injections, Intraperitoneal, Mice, Mice, Inbred C57BL, Neural Networks, Computer, Psychotropic Drugs, Pyrimidines, ROC Curve, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Small Molecule Libraries
Added May 19, 2014
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21 MeSH Terms
Synthesis and pharmacological characterization of a novel sigma receptor ligand with improved metabolic stability and antagonistic effects against methamphetamine.
Seminerio MJ, Robson MJ, Abdelazeem AH, Mesangeau C, Jamalapuram S, Avery BA, McCurdy CR, Matsumoto RR
(2012) AAPS J 14: 43-51
MeSH Terms: Administration, Oral, Animals, Behavior, Animal, Benzothiazoles, Binding Sites, Central Nervous System Stimulants, Dose-Response Relationship, Drug, Half-Life, Injections, Intraperitoneal, Ligands, Male, Methamphetamine, Mice, Motor Activity, Piperazines, Protein Binding, Radioligand Assay, Receptors, sigma, Sulfur Compounds
Show Abstract · Added July 10, 2013
Methamphetamine interacts with sigma receptors at physiologically relevant concentrations suggesting a potential site for pharmacologic intervention. In the present study, a previous sigma receptor ligand, CM156, was optimized for metabolic stability, and the lead analog was evaluated against the behavioral effects of methamphetamine. Radioligand binding studies demonstrated that the lead analog, AZ66, displayed high nanomolar affinity for both sigma-1 and sigma-2 receptors (2.4 ± 0.63 and 0.51 ± 0.15, respectively). In addition, AZ66 had preferential affinity for sigma receptors compared to seven other sites and a significantly longer half-life than its predecessor, CM156, in vitro and in vivo. Pretreatment of male, Swiss Webster mice with intraperitoneal (10-20 mg/kg) or oral (20-30 mg/kg) dosing of AZ66 significantly attenuated the acute locomotor stimulatory effects of methamphetamine. Additionally, AZ66 (10-20 mg/kg, i.p.) significantly reduced the expression and development of behavioral sensitization induced by repeated methamphetamine administration. Taken together, these data indicate that sigma receptors can be targeted to mitigate the acute and subchronic behavioral effects of methamphetamine and AZ66 represents a viable lead compound in the development of novel therapeutics against methamphetamine-induced behaviors.
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19 MeSH Terms
Synthesis and pharmacological evaluation of 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a cocaine antagonist, in rodents.
Kaushal N, Robson MJ, Vinnakota H, Narayanan S, Avery BA, McCurdy CR, Matsumoto RR
(2011) AAPS J 13: 336-46
MeSH Terms: Administration, Oral, Animals, Benzoxazoles, Cocaine, Cytochrome P-450 Enzyme System, Drug Interactions, Half-Life, Injections, Intraperitoneal, Ligands, Male, Mice, Motor Activity, Piperazines, Protein Binding, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Serotonin, 5-HT2, Receptors, sigma, Seizures
Show Abstract · Added July 10, 2013
Cocaine interacts with monoamine transporters and sigma (σ) receptors, providing logical targets for medication development. In the present study, in vitro and in vivo pharmacological studies were conducted to characterize SN79, a novel compound which was evaluated for cocaine antagonist actions. Radioligand binding studies showed that SN79 had a nanomolar affinity for σ receptors and a notable affinity for 5-HT(2) receptors, and monoamine transporters. It did not inhibit major cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP2C19, CYP2C9*1, CYP2D6, and CYP3A4, suggesting a low propensity for potential drug-drug interactions. Oral administration of SN79 reached peak in vivo concentrations after 1.5 h and exhibited a half-life of just over 7.5 h in male, Sprague-Dawley rats. Behavioral studies conducted in male, Swiss Webster mice, intraperitoneal or oral dosing with SN79 prior to a convulsive or locomotor stimulant dose of cocaine led to a significant attenuation of cocaine-induced convulsions and locomotor activity. However, SN79 produced sedation and motor incoordination on its own at higher doses, to which animals became tolerant with repeated administration. SN79 also significantly attenuated the development and expression of the sensitized response to repeated cocaine exposures. The ability of SN79 to significantly attenuate the acute and subchronic effects of cocaine provides a promising compound lead to the development of an effective pharmacotherapy against cocaine.
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20 MeSH Terms