Endocrine Abstracts

Neurogenesis, a process by which new neurons are generated from precursors, still persists in discrete regions of the adult hippocampus. The hippocampus is critical for learning and memory and is a main target of 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 AD-induced cognitive decline. Growth hormone-releasing hormone (GHRH), apart from promoting growth hormone (GH) secretion from the pituitary, exerts many extrapituitary functions, including stimulation of cell survival, cardioprotection and protection against diabetic retinopathy. 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 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 (Aβ₁–₄₂)-induced toxicity, and to define the underlying mechanisms. We found expression of both mRNA and protein for pituitary GHRH-R in NSCs. GHRH dose-dependently increased cell survival and proliferation and reduced apoptosis in NSCs cultured under both growth factor deprivation and exposure to Aβ₁–₄₂; these effects were blocked by the GHRH antagonist JV-1–36. The underlying mechanisms involved Gα_S/cAMP/PKA/CREB signaling, as demonstrated the results obtained in the presence of specific inhibitors, and phosphorylation of ERK1/2 and PI3K/Akt. In addition, GHRH counteracted the effect of Aβ₁–₄₂ on elevation of the proapoptotic protein BAX and inhibition of the antiapoptotic protein Bcl-2. Moreover, GHRH induced GSK-3β phosphorylation and counteracted the Aβ₁–₄₂-induced inhibition of GSK-3β phosphorylation. Finally, the role of GHRH was examined on differentiation of NSCs into neuronal lineages, such as neurons, oligodendrocytes, and astrocytes. Interestingly, GHRH increased the mRNA levels of the neuronal marker Tuj1, while showing no significant effect on GFAP and Ripk1, specific for astrocytes and oligodendrocytes, respectively. Collectively, these results suggest a role for GHRH in preventing neuronal loss and in promoting neurogenesis, with potential therapeutic application of its agonistic analogs in neurodegenerative diseases, such as AD.