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Molecular Medicine

, Volume 21, Issue 1, pp 505–514 | Cite as

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

  • Aviv Cohen
  • Jenny Lerner-Yardeni
  • David Meridor
  • Roni Kasher
  • Ilana Nathan
  • Abraham H. Parola
Research Article

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.

Notes

Acknowledgments

The authors thank Mark M Karpasas and Lina Saveliev from the Analytical Research Services Unit, Ben-Gurion University of the Negev, for mass spectrometric analysis of the peptides, and Svetlana Lublinsky from the Brain Imaging Center, Ben-Gurion University of the Negev, for magnetic resonance imaging of the mice. The financial support of the Kamin Program from the Chief Scientist of the Ministry of Economy of Israel (to AH Parola, I Nathan, and R Kasher), the James-Frank Center for Laser-Matter Interaction (to A H Parola), the Edmund Safra Foundation for Functional Bio-polymer, the New-York University Shanghai (NYUSH) research grant (to AH Parola) and the Lyonel Israels’ Chair Fund (I Nathan) are gratefully acknowledged.

Supplementary material

10020_2015_2101505_MOESM1_ESM.pdf (238 kb)
Supplementary material, approximately 238 KB.

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Authors and Affiliations

  • Aviv Cohen
    • 1
  • Jenny Lerner-Yardeni
    • 1
  • David Meridor
    • 1
  • Roni Kasher
    • 2
  • Ilana Nathan
    • 3
    • 4
  • Abraham H. Parola
    • 1
  1. 1.Department of Chemistry, The Faculty of Natural SciencesBen-Gurion University of the NegevBe’er-ShevaIsrael
  2. 2.Department of Desalination and Water Treatment, Zuckerberg Institute for Water Research, The Blaustein Institutes for Desert ResearchBen-Gurion University of the Negev. Midreshet Sede BoqerMidreshet Ben-GurionIsrael
  3. 3.Department of Clinical Biochemistry and Pharmacology, the Faculty of Health SciencesBen-Gurion University of the Negev.Be’er-ShevaIsrael
  4. 4.Institute of HematologySoroka University Medical CenterBe’er-ShevaIsrael

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