Proliferative and protective effects of growth hormone secretagogues on adult rat hippocampal progenitor cells.
Progenitor cells in the subgranular zone of the hippocampus may be of significance for functional recovery after various injuries because they have a regenerative potential to form new neuronal cells. The hippocampus has been shown to express the GH secretagogue (GHS) receptor 1a, and recent studies suggest GHS to both promote neurogenesis and have neuroprotective effects. The aim of the present study was to investigate whether GHS could stimulate cellular proliferation and exert cell protective effects in adult rat hippocampal progenitor (AHP) cells. Both hexarelin and ghrelin stimulated increased incorporation of (3)H-thymidine, indicating an increased cell proliferation. Furthermore, hexarelin, but not ghrelin, showed protection against growth factor deprivation-induced apoptosis, as measured by annexin V binding and caspase-3 activity and also against necrosis, as measured by lactate dehydrogenase release. Hexarelin activated the MAPK and the phosphatidylinositol 3-kinase/Akt pathways, whereas ghrelin activated only the MAPK pathway. AHP cells did not express the GHS receptor 1a, but binding studies could show specific binding of both hexarelin and ghrelin, suggesting effects to be mediated by an alternative GHS receptor subtype. In conclusion, our results suggest a differential effect of hexarelin and ghrelin in AHP cells. We have demonstrated stimulation of (3)H-thymidine incorporation with both hexarelin and ghrelin. Hexarelin, but not ghrelin, also showed a significant inhibition of apoptosis and necrosis. These results suggest a novel cell protective and proliferative role for GHS in the central nervous system.
Johansson
Inger
I
Laboratory of Experimental Endocrinology, Sahlgrenska Academy, University of Göteborg, SE-413 45 Göteborg, Sweden. inger.johansson@medic.gu.se
Destefanis
Silvia
S
Aberg
N David
ND
Aberg
Maria A I
MA
Blomgren
Klas
K
Zhu
Changlian
C
Ghè
Corrado
C
Granata
Riccarda
R
Ghigo
Ezio
E
Muccioli
Giampiero
G
Eriksson
Peter S
PS
Isgaard
Jörgen
J
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D054439:Ghrelin / Q000031:analogs & derivatives / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology
D054439:Ghrelin; D009842:Oligopeptides; D054440:Receptors, Ghrelin; C086184:hexarelin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3