Progenitor cells in the sub granular zone of the hippocampus may be of significance for functional recovery after various injuries, as they have a regenerative potential to form new neuronal cells. The hippocampus has been shown to express the growth hormone secretagogue (GHS) receptor 1a (GHS-R1a) and recent studies suggest GHS to both promote neurogenesis and to 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 ³H-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 mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways whereas ghrelin only activated the MAPK pathway. AHP cells did not express the GHS-R1a, 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 ³H-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 CNS.