A Novel iron-chelating derivative of the neuroprotective peptide NAPVSIPQ shows superior antioxidant and antineurodegenerative capabilities.
Affecting an estimated 5% of adults over 65 years of age, Parkinson's disease and Alzheimer's disease are the most common neurodegenerative disorders. Accumulating evidence suggests that oxidative stress induced by the breakdown of iron homeostasis is a major contributor to the neuronal loss observed in neurodegeneration. Thus, brain-permeable iron chelators may present potential therapeutic benefits. In the present study, iron-chelating hydroxamate groups were introduced into the NAP (NAPVSIPQ) peptide, whose neuroprotective qualities have been widely demonstrated. Our experiments revealed that the novel dihydroxamate peptide 3 is capable of inhibiting iron-catalyzed hydroxyl radical formation and lipid peroxidation, abilities that are not part of the repertoire of its parent peptide. In addition, peptide 3 was superior to native NAP in protecting human neuroblastoma cell cultures against the toxicity of hydrogen peroxide. These results suggest that NAP-based iron chelators deserve further investigation in the search for drug candidates for neurodegeneration.
Blat
Dan
D
Department of Organic Chemistry and Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel.
Weiner
Lev
L
Youdim
Moussa B H
MB
Fridkin
Mati
M
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005290:Ferric Compounds / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000737:chemistry; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D005290:Ferric Compounds; D005296:Ferrous Compounds; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; C526805:N-hydroxyasparagyl-alalnyl-prolyl-valyl-seryl-isoleucyl-prolyl-glutamine hydroxamic acid; D018696:Neuroprotective Agents; D009842:Oligopeptides; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; C425904:davunetide