• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    A mouse without kynurenine aminotransferase II: Investigating the kynurenine pathway

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Find Full text
    Author
    Sapko, Michael Todd
    Advisor
    Schwarcz, Robert
    Date
    2004
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Kynurenic acid (KYNA) is a neuroprotective metabolite of tryptophan present at sub-micromolar concentrations in mammalian brain. KYNA is an antagonist of excitatory neurotransmitter receptors with particularly high affinity for the glycine site of the NMDA receptor and the alpha7 nicotinic acetylcholine receptor. In order to study KYNA's role in brain function, this dissertation details the characterization of a null mutant mouse for kynurenine aminotransferase II (KAT II) designated mkat-2-/- . While both Western Blot analysis and PCR verified the absence of KAT II in various tissues including brain, mkat-2-/- animals had lower KAT activity in brain only at postnatal day (PND) 7 and 14, but not later in life. Brain KYNA levels were 40-60% of wild-type levels in mkat-2-/- animals before PND 28 while adult (2 to 18 months) levels were not different between genotypes. In liver, KYNA levels were over 90% lower in mkat-2 -/- animals throughout life. Brain and liver kynurenine, 3-hydroxykynurenine and quinolinic acid (QUIN) were present at levels similar to wild-type at all ages tested. mkat-2-/- were viable, developed normally, and had normal litter sizes and longevity. Behavioral deficits were observed in young but not adult mkat-2-/- mice, specifically increased locomotor activity and decreased latency to fall from a rotarod apparatus. In order to determine the relevance of endogenous KYNA to excitotoxic processes, we infused various excitotoxins into the striatum and quantified cell death. Intrastriatal injection of QUIN resulted in significantly larger lesion in mkat-2-/- compared to wild-type mice at PND 14, i.e. when brain KYNA levels are reduced ∼60%. This heightened vulnerability was not seen at 2 months, when brain KYNA concentrations in mutant mice were normal. Moreover, when a kynurenine 3-hydroxylase inhibitor, UPF 648, was used to restore KYNA levels in PND 14 mkat-2-/- mice, the increased QUIN toxicity was blocked. The influence of KYNA on excitotoxic vulnerability was specific to QUIN, as the lesion caused by an intrastriatal kainic acid or NMDA injection was not different in the two genotypes, regardless of age. Therefore, brain KYNA influences both behavior and neurotoxic processes in mouse. Further, pharmacological up-regulation of brain KYNA may offer a new venue for the treatment of human brain diseases.
    Description
    University of Maryland, Baltimore. Neuroscience. Ph.D. 2004
    Keyword
    Biology, Neuroscience
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1121
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.