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  1. AU="Reddi, Jyoti M"
  2. AU=Zeissig Sebastian
  3. AU="Valentini, Mariaconsuelo"

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  1. Artikel ; Online: AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability.

    Lykens, Nicole M / Coughlin, David J / Reddi, Jyoti M / Lutz, Gordon J / Tallent, Melanie K

    PloS one

    2017  Band 12, Heft 2, Seite(n) e0171538

    Abstract: Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. ... ...

    Abstract Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models. GluA1-flip produces higher gain AMPA channels than GluA1-flop, increasing network excitability and seizure susceptibility. Splice modulating oligonucleotides (SMOs) bind to pre-mRNA to influence alternative splicing, a strategy that can be exploited to develop more selective drugs across therapeutic areas. We developed a novel SMO, GR1, which potently and specifically decreased GluA1-flip expression throughout the brain of neonatal mice lasting at least 60 days after single intracerebroventricular injection. GR1 treatment reduced AMPA-R mediated excitatory postsynaptic currents at hippocampal CA1 synapses, without affecting long-term potentiation or long-term depression, cellular models of memory, or impairing GluA1-dependent cognition or motor function in mice. Importantly, GR1 demonstrated anti-seizure properties and reduced post-seizure hyperexcitability in neonatal mice, highlighting its drug candidate potential for treating epilepsies and other neurological diseases involving network hyperexcitability.
    Mesh-Begriff(e) Alternative Splicing ; Animals ; Animals, Newborn ; Base Sequence ; Cognition ; Disease Models, Animal ; Disease Susceptibility ; Female ; Hippocampus/metabolism ; Hippocampus/physiopathology ; Male ; Mice ; Motor Activity ; Oligonucleotides/administration & dosage ; Oligonucleotides/chemistry ; Pyramidal Cells/metabolism ; Receptors, AMPA/genetics ; Seizures/genetics ; Seizures/physiopathology ; Seizures/therapy ; Synaptic Transmission/genetics
    Chemische Substanzen Oligonucleotides ; Receptors, AMPA ; glutamate receptor ionotropic, AMPA 1 (TFZ3H25BS1)
    Sprache Englisch
    Erscheinungsdatum 2017-02-08
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0171538
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses.

    Fahey, Jeanne M / Grassi, Jeffrey M / Reddi, Jyoti M / Greenblatt, David J

    Pharmacology, biochemistry, and behavior

    2006  Band 83, Heft 1, Seite(n) 21–27

    Abstract: Zolpidem is chemically unrelated to classical benzodiazepines but has demonstrated relatively high affinity binding to the alpha(1) GABA(A) receptor. To assess pharmacodynamic and neurochemical effects of zolpidem, open-field behavior, pentylenetetrazole- ...

    Abstract Zolpidem is chemically unrelated to classical benzodiazepines but has demonstrated relatively high affinity binding to the alpha(1) GABA(A) receptor. To assess pharmacodynamic and neurochemical effects of zolpidem, open-field behavior, pentylenetetrazole-induced seizure threshold and benzodiazepine receptor binding in vitro were evaluated in the same animal following a single dose of zolpidem. Zolpidem (2, 5 and 10 mg/kg), lorazepam (2 mg/kg) or vehicle was administered intraperitoneally in male CD-1 mice. Behavioral activity, assessed by three open-field parameters, was decreased following the two highest doses of zolpidem (5 and 10 mg/kg), and reached significance at the 10 mg/kg dose. Locomotor activity was also decreased significantly by lorazepam as expected. Pentylenetetrazole-induced seizure threshold was increased with the administration of 2 and 10 mg/kg zolpidem as well as with lorazepam. Apparent affinity (K(D)) of [3H]flunitrazepam, a non-selective ligand, for the benzodiazepine receptor in cortical membrane preparations was not significantly changed, while receptor number (Bmax) was decreased at all doses of zolpidem, reaching significance at the 10 mg/kg dose. These results confirm that the behavioral effects of zolpidem are similar to those of classical benzodiazepines. In addition, zolpidem had no significant effect on the affinity of the benzodiazepine receptor for [3H]flunitrazepam, but did decrease the density of receptor binding sites.
    Mesh-Begriff(e) Animals ; Anticonvulsants ; Binding, Competitive/drug effects ; Convulsants/pharmacology ; Dose-Response Relationship, Drug ; Flunitrazepam/pharmacokinetics ; Hypnotics and Sedatives/pharmacokinetics ; Hypnotics and Sedatives/pharmacology ; Lorazepam/pharmacology ; Male ; Mice ; Motor Activity/drug effects ; Pentylenetetrazole/pharmacology ; Pyridines/pharmacokinetics ; Pyridines/pharmacology ; Receptors, Drug/drug effects ; Receptors, GABA-A/drug effects ; Seizures/chemically induced ; Seizures/physiopathology
    Chemische Substanzen Anticonvulsants ; Convulsants ; Hypnotics and Sedatives ; Pyridines ; Receptors, Drug ; Receptors, GABA-A ; Flunitrazepam (620X0222FQ) ; zolpidem (7K383OQI23) ; Lorazepam (O26FZP769L) ; Pentylenetetrazole (WM5Z385K7T)
    Sprache Englisch
    Erscheinungsdatum 2006-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 191042-5
    ISSN 1873-5177 ; 0091-3057
    ISSN (online) 1873-5177
    ISSN 0091-3057
    DOI 10.1016/j.pbb.2005.12.006
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: The effect of chronic lorazepam administration in aging mice.

    Fahey, Jeanne M / Pritchard, Gary A / Reddi, Jyoti M / Pratt, John S / Grassi, Jeffrey M / Shader, Richard I / Greenblatt, David J

    Brain research

    2006  Band 1118, Heft 1, Seite(n) 13–24

    Abstract: To assess benzodiazepine tolerance in aged animals, lorazepam or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice. Pharmacodynamic and neurochemical endpoints were examined on days 1 and 14 of drug administration. There was no age- ... ...

    Abstract To assess benzodiazepine tolerance in aged animals, lorazepam or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice. Pharmacodynamic and neurochemical endpoints were examined on days 1 and 14 of drug administration. There was no age-related significant difference in plasma lorazepam levels. Young and middle-aged animals demonstrated behavioral tolerance to lorazepam, while the aged animals showed a similar trend which failed to reach significance. In addition, aged animals also showed a trend toward tolerance to the anticonvulsant effects of lorazepam. There were no changes in alpha1 mRNA levels in cortex or hippocampus following administration of lorazepam when compared to vehicle-treated animals in any age group. Aged animals, however, had an initial increase in alpha1 mRNA expression in cortex and hippocampus on day 1 of vehicle treatment followed by decreased expression on day 14. These age-related changes were abolished by lorazepam administration. In summary, age-related sensitivity to the effects of lorazepam was not demonstrated in the present study. However, comparison of these data to other studies indicates that the effect of chronic benzodiazepine treatment may be specific to the benzodiazepine administered, the technique used to quantify mRNA expression changes, the subunits of the GABA(A) receptor investigated and the brain region analyzed. The phenomenon of benzodiazepine sensitivity in the elderly is an area of research which remains controversial and may well be compound specific. Determining benzodiazepines that do not produce pharmacodynamic sensitivity, such as lorazepam, may allow more careful prescribing and dosing of these drugs, and perhaps even the development of specific agents which could avoid this sensitivity.
    Mesh-Begriff(e) Aging/physiology ; Animals ; Brain/drug effects ; Brain/metabolism ; Cerebral Cortex/drug effects ; Cerebral Cortex/metabolism ; Convulsants/pharmacology ; Drug Administration Schedule ; Drug Interactions/physiology ; Drug Tolerance/physiology ; GABA Modulators/blood ; GABA Modulators/toxicity ; Hippocampus/drug effects ; Hippocampus/metabolism ; Lorazepam/blood ; Lorazepam/toxicity ; Male ; Mice ; No-Observed-Adverse-Effect Level ; RNA, Messenger/drug effects ; RNA, Messenger/metabolism ; Receptors, GABA-A/genetics ; Seizures/chemically induced ; Seizures/drug therapy ; Seizures/metabolism
    Chemische Substanzen Convulsants ; GABA Modulators ; Gabra1 protein, mouse ; RNA, Messenger ; Receptors, GABA-A ; Lorazepam (O26FZP769L)
    Sprache Englisch
    Erscheinungsdatum 2006-11-06
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2006.08.017
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

    Volltext online

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 161: Hefte anzeigen Standort:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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