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.
Keywords:
Glutathione; glyoxalase I; Alzheimer’s disease; β-amyloid peptide; methylglyoxal; advanced glycation end products
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