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Proliferative and Protective Effects of Growth Hormone Secretagogues on Adult Rat Hippocampal Progenitor Cells

Laboratory of Experimental Endocrinology (I.J., S.D., N.D.A., J.I.), Department of Internal Medicine, and Center of Brain Repair and Rehabilitation (M.A.I.A., K.B., C.Z., P.S.E.), Sahlgrenska Academy, University of Göteborg, Göteborg SE-413 45, Sweden; and Department of Internal Medicine (R.G., E.G.), University of Turin, 10126 Turin, Italy; and Division of Pharmacology, Department of Anatomy (S.D., C.G., G.M.), Pharmacology, and Forensic Medicine, University of Turin, 10135 Turin, Italy

Address all correspondence and requests for reprints to: Inger Johansson, B.Sc., Laboratory of Experimental Endocrinology, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: inger.johansson{at}medic.gu.se.

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 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 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 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 central nervous system.