Endocrine Abstracts

Neurogenesis, the process by which new neurons are generated from precursors, persists in discrete regions of the adult hippocampus. The hippocampus is critical for learning and memory and is the main target of Alzheimer’s Disease (AD), which causes massive neuronal death, reduction in neurogenesis, and impairment in cognitive functions. Therefore, preventing neuronal loss or increasing the production of new neurons may represent a potential therapeutic strategy to reduce the AD-induced cognitive decline. Growth hormone-releasing hormone (GHRH) and its agonistic analogs, apart from promoting growth hormone (GH) secretion from the pituitary, exert many peripheral functions, including stimulation of cell survival, cardioprotection and neuroprotection. Furthermore, expression of GHRH, as well as GHRH-receptor (GHRH-R) and its splice variants (SVs), has been demonstrated in different brain regions, including the cerebral cortex, cerebellum, hippocampus, and brain stem cells. To date, however, the role of GHRH on neurogenesis and neuroprotection is still unknown. Thus, we aimed to investigate the role of GHRH on survival, proliferation, apoptosis, and differentiation of rat hippocampal neural stem cells (NSCs), in stress conditions such as growth factor deprivation and amyloid-β peptide 1-42 (Aβ_1-42)-induced toxicity, and to define the underlying mechanisms. We found the expression of both mRNA and protein for pituitary GHRH-R in NSCs. GHRH dose-dependently increased cell survival and proliferation, while reducing apoptosis in NSCs cultured under both growth factor deprivation and exposure to Aβ_1-42. These effects were blocked by the GHRH-R antagonist JV-1-36. The underlying mechanisms involved G_αS/cAMP/PKA/CREB signaling, as demonstrated using specific inhibitors, and phosphorylation of ERK1/2, PI3K/Akt, and GSK-3β but not mTOR/p70S6K. Furthermore, GHRH counteracted the Aβ_1-42-induced phosphorylation of Tau protein and the inhibition of GSK-3β phosphorylation. GHRH also blocked the effect of Aβ_1-42 on elevation of the proapoptotic protein BAX and on inhibition of the antiapoptotic protein Bcl-2. In addition, our preliminary results suggest an antinflammatory role of GHRH, via inhibition in the mRNA levels of inflammatory cytokines (IL-6, TNF-α, INF-γ) and ROS activity. Finally, the role of GHRH was investigated on the differentiation of NSCs into neuronal lineages, such as neurons, astrocytes, and oligodendrocytes. Interestingly, GHRH increased the mRNA and protein levels of the neuronal marker Tuj1/NeuN and the astrocytes marker GFAP while showing no effect on the oligodendrocyte marker Ripk1. Collectively, these results indicate a role for GHRH in preventing neuronal loss and promoting neurogenesis, suggesting therapeutic potential for its agonistic analogs in neurodegenerative diseases, such as AD.