Novel humanin analogs confer neuroprotection and myoprotection to neuronal and myoblast cell cultures exposed to ischemia-like and doxorubicin-induced cell death insults.

Abstract

Humanin (HN) is a 24-amino acid mitochondrial-derived peptide, best known for its ability to protect neurons from damage caused by ischemic stroke and neurodegenerative insults and cardiomyocytes from myocardial infarction or doxorubicin (Dox)-induced cardiotoxicity. This study examines the neuroprotective and myoprotective effects of HN novel synthetic analogs HUJInin and c(D-Ser14-HN), prepared by solid-phase peptide synthesis. The cellular models employed were oxygen-glucose-deprivation (OGD) followed by reoxygenation (R)-induced neurotoxicity in PC12 and SH-SY5Y neuronal cell cultures and Dox-induced cardiotoxicity in H9c2 and C2C12 myoblast cell cultures, respectively. Necrotic and apoptotic cell death was measured by LDH release and caspase-3 activity. Erk 1/2 and AKT phosphorylations were examined by western blotting. Mitochondrial calcium and mitochondrial membrane potential were measured using the fluorescent dye tetramethylrhodamine-methyl ester. It was found that HUJInin and c(D-Ser14-HN) conferred significant dose-dependent neuroprotection, a phenomenon related to attenuation of OGD insult-induced Erk 1/2 phosphorylation, stimulation of AKT phosphorylation and improvement of mitochondrial functions. These peptides also conferred myoprotective effect towards Dox-induced apo-necrotic cell death insults. HUJInin and c(D-Ser14-HN) synthetic analogs may provide new lead compounds for the development of a potential candidate drug for stroke treatment and/or Dox-induced cardiotoxicity therapy in cancer patients.

• Authors: Chaim Gilon, Agata Gitlin-Domagalska, Adi Lahiani, Shiran Yehoshua-Alshanski, Adi Shumacher-Klinger, Dan Gilon, Mahmoud Taha, Israel Sekler, Amnon Hoffman, Philip Lazarovici
• Journal: Peptides (Peptides) Vol. 134 Pg. 170399 (12 2020) ISSN: 1873-5169 [Electronic] United States
• PMID: 32889021 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Antibiotics, Antineoplastic
• Intracellular Signaling Peptides and Proteins
• Neuroprotective Agents
• humanin
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Apoptosis (drug effects)
• Cells, Cultured
• Doxorubicin (toxicity)
• Humans
• Intracellular Signaling Peptides and Proteins (chemistry, pharmacology)
• Ischemia (physiopathology)
• Mice
• Mitochondria (drug effects, metabolism, pathology)
• Myoblasts (drug effects, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (chemistry, pharmacology)
• Phosphorylation
• Rats