Sulfanegen stimulates 3-mercaptopyruvate sulfurtransferase activity and ameliorates Alzheimer's disease pathology and oxidative stress in vivo

Swetha Pavani Rao, Wei Xie, Nicholas Juckel, Ye In Christopher Kwon, Jiashu Xie, Venkateshwara Rao Dronamraju, Robert Vince, Michael K. Lee, Swati S. More

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1 Scopus citations

Abstract

Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) and H2S donors such as sodium hydrosulfide (NaSH) can reduce oxidative stress in preclinical studies, however clinical benefits of such treatments are rather ambiguous. This is partly due to poor stability and bioavailability of the H2S donors, requiring impractically large doses that are associated with dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which is able to pose as a sacrificial redox substrate for 3-mercaptopyruvate sulfurtransferase (3MST), one of the H2S biosynthetic enzymes in the brain. Sulfanegen is able to mitigate toxicity emanating from oxidative insults and the Aβ1-42 peptide by releasing H2S through the 3MST pathway. When administered to symptomatic transgenic mouse model of AD (APP/PS1; 7 and 12 months) and mice that were intracerebroventricularly administered with the Aβ1-42 peptide, sulfanegen was able to reverse oxidative and neuroinflammatory consequences of AD pathology by restoring 3MST function. Quantitative neuropathological analyses confirmed significant disease modifying effect of the compound on amyloid plaque burden and brain inflammatory markers. More importantly, sulfanegen treatment attenuated progressive neurodegeneration in these mice, as evident from the restoration of TH+ neurons in the locus coeruleus. This study demonstrates a previously unknown concept that supplementation of 3MST function in the brain may be a viable approach for the management of AD. Finally, brought into the spotlight is the potential of sulfanegen as a promising AD therapeutic for future drug development efforts.

Original languageEnglish (US)
Article number102484
JournalRedox Biology
Volume57
DOIs
StatePublished - Nov 2022

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health Grants to SSM ( R01-AG062469 ) and MKL ( RF1-AG062135 , R01-NS108686 ) and by funding from the Center for Drug Design (CDD), University of Minnesota .

Publisher Copyright:
© 2022 The Authors

Keywords

  • 3MST
  • Alzheimer's disease
  • Hydrogen sulfide
  • Neurodegeneration
  • Neuroinflammation
  • Sulfanegen

PubMed: MeSH publication types

  • Journal Article

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