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Ghrelin, an endogenous ligand for the GH secretagogue receptor (GHS-R) receptor 1a (GHS-R1a), has been implicated in several physiologic processes involving the hippocampus. The aim of this study was to investigate the molecular mechanisms of ghrelin-stimulated neurogenesis using cultured adult rat hippocampal neural stem cells (NSCs). The expression of GHS-R1a was detected in hippocampal NSCs, as assessed by western blot analysis and immunocytochemistry. Ghrelin treatment increased the proliferation of cultured hippocampal NSCs assessed by BrdU incorporation. The exposure of cells to the receptor-specific antagonist D-Lys-3-GHRP-6 abolished the proliferative effect of ghrelin. By contrast, ghrelin showed no significant effect on cell differentiation. The expression of GHS-R1a was significantly increased by ghrelin treatment. The analysis of signaling pathways showed that ghrelin caused rapid activation of ERK1/2 and Akt, which were blocked by the GHS-R1a antagonist. In addition, ghrelin stimulated the phosphorylation of Akt downstream effectors, such as glycogen synthase kinase (GSK)-3b, mammalian target of rapamycin (mTOR), and p70 S6K. The activation of STAT3 was also caused by ghrelin treatment. Furthermore, pretreatment of cells with specific inhibitors of MEK/ERK1/2, phosphatidylinositol-3-kinase (PI3K)/Akt, mTOR, and Jak2/STAT3 attenuated ghrelin-induced cell proliferation. Taken together, our results support a role for ghrelin in adult hippocampal neurogenesis and suggest the involvement of the ERK1/2, PI3K/Akt, and STAT3 signaling pathways in the mediation of the actions of ghrelin on neurogenesis. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3b and activation of mTOR/p70 S6K contribute to the proliferative effect of ghrelin.

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Glutamate excitotoxicity is emerging as a contributor to degeneration of spinal cord motoneurons in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin protects motoneurons against chronic glutamate excitotoxicity through the activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β pathways. Previous studies suggest that activated microglia actively participate in the pathogenesis of ALS motoneuron degeneration. However, it is still unknown whether ghrelin exerts its protective effect on motoneurons via inhibition of microglial activation. In this study, we investigate organotypic spinal cord cultures (OSCCs) exposed to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration, to determine if ghrelin prevents microglial activation. Exposure of OSCCs to THA for 3 weeks produced typical motoneuron death, and treatment of ghrelin significantly attenuated THA-induced motoneuron loss, as previously reported. Ghrelin prevented THA-induced microglial activation in the spinal cord and the expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β. Our data indicate that ghrelin may act as a survival factor for motoneurons by functioning as a microglia-deactivating factor and suggest that ghrelin may have therapeutic potential for the treatment of ALS and other neurodegenerative disorders where inflammatory responses play a critical role.

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