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Restoration of glyoxalase enzyme activity precludes cognitive dysfunction in a mouse model of Alzheimer's disease.
ACS Chem Neurosci 2013; 4(2):330-8AC

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.

Authors+Show Affiliations

Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, MN 55455, USA.No affiliation info availableNo affiliation info available

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 -