title: Humanin Derivatives Inhibit Necrotic Cell Death in Neurons.
abstract: Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer's disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide's antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide's direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17.
authors.affiliation: Department of Chemistry, The Faculty of Natural Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Department of Chemistry, The Faculty of Natural Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lerner-Yardeni
authors.affiliation: Department of Chemistry, The Faculty of Natural Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Meridor
authors.affiliation: Department of Desalination and Water Treatment, Zuckerberg Institute for Water Research, The Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Sede Boqer Campus, Midreshet Sede Boqer, Israel.
authors.forename: Roni
authors.initials: R
authors.lastname: Kasher
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, The Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.|Institute of Hematology, Soroka University Medical Center, Be'er-Sheva, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Nathan
authors.affiliation: Department of Chemistry, The Faculty of Natural Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
authors.forename: Abraham H
authors.initials: AH
authors.lastname: Parola
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001929:Brain Edema / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D001930:Brain Injuries / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000096:biosynthesis; D009336:Necrosis / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D016716:PC12 Cells; D011859:Radiography; D051381:Rats
chemical_list: C532522:AGA-(C8R)HNG17; D047908:Intracellular Signaling Peptides and Proteins; C412204:ATP synthase subunit 6; D025261:Mitochondrial Proton-Translocating ATPases