HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsAviv Cohen, Jenny Lerner-Yardeni, David Meridor, Roni Kasher, Ilana Nathan, Abraham H Parola
JournalMolecular medicine (Cambridge, Mass.) (Mol Med) Vol. 21 Pg. 505-14 (Jun 04 2015) ISSN: 1528-3658 [Electronic] England
PMID26062019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • AGA-(C8R)HNG17
  • Intracellular Signaling Peptides and Proteins
  • ATP synthase subunit 6
  • Mitochondrial Proton-Translocating ATPases
Topics
  • Alzheimer Disease (drug therapy, genetics, pathology)
  • Animals
  • Apoptosis (drug effects)
  • Brain Edema (drug therapy, genetics, pathology)
  • Brain Injuries (diagnostic imaging, drug therapy, pathology)
  • Humans
  • Intracellular Signaling Peptides and Proteins (administration & dosage)
  • Magnetic Resonance Imaging
  • Mice
  • Mitochondria (drug effects, metabolism)
  • Mitochondrial Proton-Translocating ATPases (biosynthesis)
  • Necrosis (diagnostic imaging, drug therapy, pathology)
  • Neurons (diagnostic imaging, drug effects, pathology)
  • PC12 Cells
  • Radiography
  • Rats

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: