Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice.

ABSTRACT: Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH e

SUBMITTER: Rao SP 

PROVIDER: S-EPMC11761491 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature