Tags

Type your tag names separated by a space and hit enter

Restoration of glyoxalase enzyme activity precludes cognitive dysfunction in a mouse model of Alzheimer's disease.

Abstract

Pathologically high brain levels of reactive dicarbonyls such as methylglyoxal or glyoxal initiate processes that lead ultimately to neurodegeneration, presented clinically as Alzheimer's disease and other cognitive or motor impairment disorders. Methylglyoxal and glyoxal result from glycolysis and normal metabolic pathways. Their reaction products with proteins (advanced glycation end products), and their primary chemical toxicities are both linked unequivocally to the primary pathologies of Alzheimer's disease, namely, amyloid plaques and neurofibrillary tangles. Generation of dicarbonyls is countered through the reduction of dicarbonyls by the glutathione-dependent glyoxalase enzyme system. Although glyoxalase-I is overexpressed in early and middle stages of Alzheimer's disease, glutathione depletion in the Alzheimer's afflicted brain cripples its efficacy. Due to the lack of a suitable pharmacological tool, the restoration of glyoxalase enzyme activity in pre-Alzheimer's or manifest Alzheimer's remains yet unvalidated as a means for anti-Alzheimer's therapy development. Disclosed herein are the results of a preclinical study into the therapeutic efficacy of ψ-GSH, a synthetic cofactor of glyoxalase, in mitigating Alzheimer's indicators in a transgenic mouse model (APP/PS1) that is predisposed to Alzheimer's disease. ψ-GSH administration completely averts the development of spatial mnemonic and long-term cognitive/cued-recall impairment. Amyloid β deposition and oxidative stress indicators are drastically reduced in the ψ-GSH-treated APP/PS1 mouse. ψ-GSH lacks discernible toxicity at strikingly high doses of 2000 mg/kg. The hypothesis that restoring brain glyoxalase activity would ameliorate neurogeneration stands validated, thus presenting a much needed new target for design of anti-Alzheimer's therapeutics. Consequently, ψ-GSH is established as a candidate for drug-development.

Links

  • PMC Free PDF
  • PMC Free Full Text
  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, MN 55455, USA.

    ,

    Source

    ACS chemical neuroscience 4:2 2013 Feb 20 pg 330-8

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Animals
    Behavior, Animal
    Brain
    Coenzymes
    Disease Models, Animal
    Glutathione
    Glycation End Products, Advanced
    Glyoxal
    Lactoylglutathione Lyase
    Mice
    Mice, Transgenic
    Oxidative Stress
    Plaque, Amyloid
    Pyruvaldehyde
    Structure-Activity Relationship
    Urea

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23421684

    Citation

    More, Swati S., et al. "Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease." ACS Chemical Neuroscience, vol. 4, no. 2, 2013, pp. 330-8.
    More SS, Vartak AP, Vince R. Restoration of glyoxalase enzyme activity precludes cognitive dysfunction in a mouse model of Alzheimer's disease. ACS Chem Neurosci. 2013;4(2):330-8.
    More, S. S., Vartak, A. P., & Vince, R. (2013). Restoration of glyoxalase enzyme activity precludes cognitive dysfunction in a mouse model of Alzheimer's disease. ACS Chemical Neuroscience, 4(2), pp. 330-8. doi:10.1021/cn3001679.
    More SS, Vartak AP, Vince R. Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease. ACS Chem Neurosci. 2013 Feb 20;4(2):330-8. PubMed PMID: 23421684.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Restoration of glyoxalase enzyme activity precludes cognitive dysfunction in a mouse model of Alzheimer's disease. AU - More,Swati S, AU - Vartak,Ashish P, AU - Vince,Robert, Y1 - 2012/12/04/ PY - 2013/2/21/entrez PY - 2013/2/21/pubmed PY - 2013/10/30/medline SP - 330 EP - 8 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 4 IS - 2 N2 - Pathologically high brain levels of reactive dicarbonyls such as methylglyoxal or glyoxal initiate processes that lead ultimately to neurodegeneration, presented clinically as Alzheimer's disease and other cognitive or motor impairment disorders. Methylglyoxal and glyoxal result from glycolysis and normal metabolic pathways. Their reaction products with proteins (advanced glycation end products), and their primary chemical toxicities are both linked unequivocally to the primary pathologies of Alzheimer's disease, namely, amyloid plaques and neurofibrillary tangles. Generation of dicarbonyls is countered through the reduction of dicarbonyls by the glutathione-dependent glyoxalase enzyme system. Although glyoxalase-I is overexpressed in early and middle stages of Alzheimer's disease, glutathione depletion in the Alzheimer's afflicted brain cripples its efficacy. Due to the lack of a suitable pharmacological tool, the restoration of glyoxalase enzyme activity in pre-Alzheimer's or manifest Alzheimer's remains yet unvalidated as a means for anti-Alzheimer's therapy development. Disclosed herein are the results of a preclinical study into the therapeutic efficacy of ψ-GSH, a synthetic cofactor of glyoxalase, in mitigating Alzheimer's indicators in a transgenic mouse model (APP/PS1) that is predisposed to Alzheimer's disease. ψ-GSH administration completely averts the development of spatial mnemonic and long-term cognitive/cued-recall impairment. Amyloid β deposition and oxidative stress indicators are drastically reduced in the ψ-GSH-treated APP/PS1 mouse. ψ-GSH lacks discernible toxicity at strikingly high doses of 2000 mg/kg. The hypothesis that restoring brain glyoxalase activity would ameliorate neurogeneration stands validated, thus presenting a much needed new target for design of anti-Alzheimer's therapeutics. Consequently, ψ-GSH is established as a candidate for drug-development. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/23421684/Restoration_of_glyoxalase_enzyme_activity_precludes_cognitive_dysfunction_in_a_mouse_model_of_Alzheimer's_disease_ L2 - https://dx.doi.org/10.1021/cn3001679 DB - PRIME DP - Unbound Medicine ER -