Growth Hormone (GH) Enhances Endogenous Mechanisms of Neuroprotection and Neuroplasticity after Oxygen and Glucose Deprivation Injury (OGD) and Reoxygenation (OGD/R) in Chicken Hippocampal Cell Cultures.

As a classical growth promoter and metabolic regulator, growth hormone (GH) is involved in development of the central nervous system (CNS). This hormone might also act as a neurotrophin, since GH is able to induce neuroprotection, neurite growth, and synaptogenesis during the repair process that occurs in response to neural injury. After an ischemic insult, the neural tissue activates endogenous neuroprotective mechanisms regulated by local neurotrophins that promote tissue recovery. In this work, we investigated the neuroprotective effects of GH in cultured hippocampal neurons exposed to hypoxia-ischemia injury and further reoxygenation. Hippocampal cell cultures obtained from chick embryos were incubated under oxygen-glucose deprivation (OGD, <5% O(2), 1 g/L glucose) conditions for 24 h and simultaneously treated with GH. Then, cells were either collected for analysis or submitted to reoxygenation and normal glucose incubation conditions (OGD/R) for another 24 h, in the presence of GH. Results showed that OGD injury significantly reduced cell survival, the number of cells, dendritic length, and number of neurites, whereas OGD/R stage restored most of those adverse effects. Also, OGD/R increased the mRNA expression of several synaptogenic markers (i.e., NRXN1, NRXN3, NLG1, and GAP43), as well as the growth hormone receptor (GHR). The expression of BDNF, IGF-1, and BMP4 mRNAs was augmented in response to OGD injury, and exposure to OGD/R returned it to normoxic control levels, while the expression of NT-3 increased in both conditions. The addition of GH (10 nM) to hippocampal cultures during OGD reduced apoptosis and induced a significant increase in cell survival, number of cells, and doublecortin immunoreactivity (DCX-IR), above that observed in the OGD/R stage. GH treatment also protected dendrites and neurites during OGD, inducing plastic changes reflected in an increase and complexity of their outgrowths during OGD/R. Furthermore, GH increased the expression of NRXN1, NRXN3, NLG1, and GAP43 after OGD injury. GH also increased the BDNF expression after OGD, but reduced it after OGD/R. Conversely, BMP4 was upregulated by GH after OGD/R. Overall, these results indicate that GH protective actions in the neural tissue may be explained by a synergic combination between its own effect and that of other local neurotrophins regulated by autocrine/paracrine mechanisms, which together accelerate the recovery of tissue damaged by hypoxia-ischemia.