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Novel S-acyl glutathione derivatives prevent amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models.

Abstract
Oxidative stress-mediated neuronal death may be initiated by a decrease in glutathione (GSH), whose levels are reduced in mitochondrial and synaptosomal fractions of specific CNS regions in Alzheimer disease (AD) patients. Currently, the use of GSH as a therapeutic agent is limited by its unfavorable pharmacokinetic properties. In this study, we designed the synthesis of new S-acyl glutathione (acyl-SG) thioesters of fatty acids via N-acyl benzotriazole-intermediate production and investigated their potential for targeted delivery of the parent GSH and free fatty acid to amyloid-exposed fibroblasts from familial AD patients and human SH-SY5Y neuroblastoma cells. Cell culture supplementation with acyl-SG derivatives triggers a significant decrease in lipid peroxidation and mitochondrial dysfunction in a fatty acid unsaturation degree-dependent fashion. Acyl-SG thioesters also protect cholinergic neurons against Aβ-induced damage and reduce glial reaction in rat brains. Collectively, these findings suggest that acyl-SG thioesters could prove useful as a tool for controlling AD-induced cerebral deterioration.
AuthorsMariagioia Zampagni, Daniel Wright, Roberta Cascella, Giampiero D'Adamio, Fiorella Casamenti, Elisa Evangelisti, Francesca Cardona, Andrea Goti, Benedetta Nacmias, Sandro Sorbi, Gianfranco Liguri, Cristina Cecchi
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 52 Issue 8 Pg. 1362-71 (Apr 15 2012) ISSN: 1873-4596 [Electronic] United States
PMID22326489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • Amyloid
  • Receptors, Cholinergic
  • Caspase 3
  • Glutathione
Topics
  • Amyloid (metabolism)
  • Animals
  • Brain (drug effects, pathology)
  • Caspase 3 (metabolism)
  • Cell Line, Tumor
  • Cells, Cultured
  • Enzyme Activation
  • Fluorescent Antibody Technique
  • Glutathione (pharmacology)
  • Humans
  • Models, Biological
  • Oxidative Stress (drug effects)
  • Rats
  • Receptors, Cholinergic (metabolism)

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