Johansson Inger, Destefanis Silvia, Aberg N David, Aberg Maria A I, Blomgren Klas, Zhu Changlian, Ghè Corrado, Granata Riccarda, Ghigo Ezio, Muccioli Giampiero, Eriksson Peter S, Isgaard Jörgen
Laboratory of Experimental Endocrinology, Sahlgrenska Academy, University of Göteborg, SE-413 45 Göteborg, Sweden.
Endocrinology. 2008 May;149(5):2191-9. doi: 10.1210/en.2007-0733. Epub 2008 Jan 24.
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.
海马体颗粒下区的祖细胞对于各种损伤后的功能恢复可能具有重要意义，因为它们具有形成新神经元细胞的再生潜力。海马体已被证明表达生长激素促分泌素（GHS）受体1a，最近的研究表明GHS既能促进神经发生，又具有神经保护作用。本研究的目的是调查GHS是否能刺激成年大鼠海马祖细胞（AHP）的细胞增殖并发挥细胞保护作用。六肽促生长素和胃饥饿素均刺激了（3）H-胸腺嘧啶核苷掺入量的增加，表明细胞增殖增加。此外，通过膜联蛋白V结合和半胱天冬酶-3活性测定，六肽促生长素而非胃饥饿素显示出对生长因子剥夺诱导的细胞凋亡具有保护作用，并且通过乳酸脱氢酶释放测定，对坏死也具有保护作用。六肽促生长素激活了丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）途径，而胃饥饿素仅激活了MAPK途径。AHP细胞不表达GHS受体1a，但结合研究表明六肽促生长素和胃饥饿素均有特异性结合，提示其作用可能由另一种GHS受体亚型介导。总之，我们的结果表明六肽促生长素和胃饥饿素在AHP细胞中具有不同的作用。我们已证明六肽促生长素和胃饥饿素均能刺激（3）H-胸腺嘧啶核苷掺入。六肽促生长素而非胃饥饿素还显示出对细胞凋亡和坏死有显著抑制作用。这些结果提示GHS在中枢神经系统中具有新的细胞保护和增殖作用。
