Growth hormone-releasing peptide 6 protection of hypothalamic neurons from glutamate excitotoxicity is caspase independent and not mediated by insulin-like growth factor I.
Treatment of the fetal hypothalamic neuronal cell line RCA-6 with growth hormone-releasing peptide 6, an agonist of the ghrelin receptor, or insulin-like growth factor I activates intracellular signalling cascades associated with anti-apoptotic actions. Abnormally high concentrations of glutamate provoke over-excitation of neurons leading to cell damage and apoptosis. Thus, the aim of this study was to investigate whether the administration of growth hormone-releasing peptide 6 and insulin-like growth factor I attenuates monosodium glutamate-induced apoptosis in RCA-6 neurons and the mechanisms involved. Two different mechanisms are involved in glutamate-induced cell death, one by means of caspase activation and the second through activation of a caspase-independent pathway of apoptosis mediated by the translocation of apoptosis-inducing factor. Growth hormone-releasing peptide 6 partially reversed glutamate-induced cell death but not the activation of caspases, suggesting blockage of the caspase-independent cell death pathway, which included interference with the translocation of apoptosis-inducing factor to the nucleus associated with the induction of Bcl-2. In contrast, the addition of insulin-like growth factor I to RCA-6 neurons abolished glutamate-induced caspase activation and cell death. These data demonstrate for the first time a neuroprotective role for growth hormone secretagogues in the caspase-independent cell death pathway and indicate that these peptides have neuroprotective effects independent of its induction of insulin-like growth factor I.
Delgado-Rubín
A
A
Department of Pediatrics, Universidad Autónoma de Madrid, Spain.
Chowen
Julie A
JA
Argente
Jesús
J
Frago
Laura M
LM
D000818:Animals; D020169:Caspases / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018846:Excitatory Amino Acids / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity*; D013007:Growth Hormone-Releasing Hormone / Q000494:pharmacology* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology* / Q000502:physiology; D051381:Rats
D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D009842:Oligopeptides; D018698:Glutamic Acid; C041048:growth hormone releasing hexapeptide; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; D020169:Caspases