Potential of a γ-Glutamyl-Transpeptidase-Stable Glutathione Analogue against Amyloid-β Toxicity

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.

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

“…ψ-GSH ( Figure S1 ) was synthesized in our laboratory using a previously described synthetic method [ 16 ]. Authentication of the compound was through NMR analysis and purity (>97% pure) of ψ-GSH was confirmed by reverse phase HPLC analysis.…”

“…Similarly, attempts to promote GSH synthesis by providing precursors also failed due to inadequate biosynthetic machinery in the aging brain [ 15 ]. We formulated and successfully tested a solution to this problem through the design and synthesis of a metabolically stable GSH analog, ψ-GSH ( Figure S1 ), which is (a) resistant to cleavage by GGT, (b) able to utilize the GSH influx transporters at the Blood Brain Barrier (BBB), (c) substitute for GSH as a cofactor in Glo (and other GSH dependent) enzyme reactions, and (d) act as an antioxidant against H 2 O 2 insult [ 16 ].…”

“…Our lead GGT-resistant GSH-analogue, ψ-GSH, protects cells from Aβ toxicity and reduces AD-related pathology (Aβ deposition, cognitive deficits, and oxidative stress) in the APP/PS1 mouse model of AD [ 16 , 17 ]. In the prior study, the ψ-GSH treatment was initiated in the 3 mo-old APP/PS1 model, well prior to the onset of neuropathology, and the animals were analyzed at a very early stage of the disease (6 months of age).…”

Quercetin protects human brain microvascular endothelial cells from fibrillar β-amyloid1–40-induced toxicity

“…Progressive build-up of A β in and around vessels induces alteration in the BBB permeability, which chronically limits blood supply and results in deprivation of oxygen and nutrients 12 , 13 . Accordingly, these changes trigger a secondary cascade of metabolic events involving generation of free radicals, oxidative stress, and release of proteases, such as γ -glutamyl transpeptidase ( γ -GT) and alkaline phosphatase (ALP) 13 , 14 , 15 . Therefore, BMECs are considered as a potential target in AD.…”

Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-Modifying Drugs. Update 2014

“…-Glutathione (psi-GSH) is a stable glutathione analogue, in which the amide bond is replaced by a ureide linkage. It crossed the blood-brain barrier via the glutathione active uptake machinery, protected cells against chemical oxidative insult and lowered the cytotoxicity of A␤ [450]. Researchers of the University of Minnesota (Minneapolis, MN) showed that the restoration of glyoxalase enzyme activity precluded cognitive dysfunction in AD mice [451].…”