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Potential of a γ-glutamyl-transpeptidase-stable glutathione analogue against amyloid-β toxicity.
ACS Chem Neurosci 2012; 3(3):204-10AC

Abstract

The antioxidant properties of glutathione (GSH) and their relevance to oxidative stress induced pathological states such as Alzheimer's disease is well-established. The utility of GSH itself as a pharmacotherapeutic agent for such disorders is limited because of the former's lability to breakdown through amide cleavage by the ubiquitous enzyme γ-glutamyl transpeptidase (γ-GT). In the present study, a GSH analogue, Ψ-GSH, where the γ-glutamylcysteine amide linkage is replaced with a ureide linkage, was synthesized. Ψ-GSH was found to be stable toward γ-GT mediated breakdown. Ψ-GSH fulfilled four cardinal properties of GSH, namely, traversing across the blood brain barrier (BBB) via the GSH active uptake machinery, replacing GSH in the glyoxalase-I mediated detoxification of methylglyoxal, protecting cells against chemical oxidative insult, and finally lowering the cytotoxicity of amyloid-β peptide. These results validate Ψ-GSH as a viable metabolically stable replacement for GSH and establish it as a potential preclinical candidate for treatment of oxidative stress mediated pathology.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

22860189

Citation

More, Swati S., and Robert Vince. "Potential of a Γ-glutamyl-transpeptidase-stable Glutathione Analogue Against Amyloid-β Toxicity." ACS Chemical Neuroscience, vol. 3, no. 3, 2012, pp. 204-10.
More SS, Vince R. Potential of a γ-glutamyl-transpeptidase-stable glutathione analogue against amyloid-β toxicity. ACS Chem Neurosci. 2012;3(3):204-10.
More, S. S., & Vince, R. (2012). Potential of a γ-glutamyl-transpeptidase-stable glutathione analogue against amyloid-β toxicity. ACS Chemical Neuroscience, 3(3), pp. 204-10. doi:10.1021/cn200113z.
More SS, Vince R. Potential of a Γ-glutamyl-transpeptidase-stable Glutathione Analogue Against Amyloid-β Toxicity. ACS Chem Neurosci. 2012 Mar 21;3(3):204-10. PubMed PMID: 22860189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potential of a γ-glutamyl-transpeptidase-stable glutathione analogue against amyloid-β toxicity. AU - More,Swati S, AU - Vince,Robert, Y1 - 2012/01/03/ PY - 2011/11/15/received PY - 2012/01/03/accepted PY - 2012/8/4/entrez PY - 2012/8/4/pubmed PY - 2012/8/4/medline KW - Alzheimer’s disease KW - Glutathione KW - advanced glycation end products KW - glyoxalase I KW - methylglyoxal KW - β-amyloid peptide SP - 204 EP - 10 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 3 IS - 3 N2 - The antioxidant properties of glutathione (GSH) and their relevance to oxidative stress induced pathological states such as Alzheimer's disease is well-established. The utility of GSH itself as a pharmacotherapeutic agent for such disorders is limited because of the former's lability to breakdown through amide cleavage by the ubiquitous enzyme γ-glutamyl transpeptidase (γ-GT). In the present study, a GSH analogue, Ψ-GSH, where the γ-glutamylcysteine amide linkage is replaced with a ureide linkage, was synthesized. Ψ-GSH was found to be stable toward γ-GT mediated breakdown. Ψ-GSH fulfilled four cardinal properties of GSH, namely, traversing across the blood brain barrier (BBB) via the GSH active uptake machinery, replacing GSH in the glyoxalase-I mediated detoxification of methylglyoxal, protecting cells against chemical oxidative insult, and finally lowering the cytotoxicity of amyloid-β peptide. These results validate Ψ-GSH as a viable metabolically stable replacement for GSH and establish it as a potential preclinical candidate for treatment of oxidative stress mediated pathology. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/22860189/Potential_of_a_γ_glutamyl_transpeptidase_stable_glutathione_analogue_against_amyloid_β_toxicity_ L2 - https://dx.doi.org/10.1021/cn200113z DB - PRIME DP - Unbound Medicine ER -