Oral Prodrug of a Novel Glutathione Surrogate Reverses Metabolic Dysregulation and Attenuates Neurodegenerative Process in Transgenic Alzheimer’s Mice

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 nonenzymatic
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 effectively
reversed the cognitive decline observed in the APP/PS1 mouse model.
The prodrug successfully mirrors the robust effects of the parent
drug, i.e., reducing amyloid pathology, glycation stress, neuroinflammation,
and the resultant neurodegeneration, in these mice. We also report
the first metabolomics study of such a treatment that yields key biomarkers
linked to the reversal of AD-related metabolic dysregulation. Collectively,
this study demonstrates the neuroprotective effect of pro-ψ-GSH
in a symptomatic preclinical model of AD and paves the way for further
preclinical advancement of such therapeutics. Metabolomic signatures
identified could prove beneficial in the development of treatment-specific,
clinically translatable biomarkers.