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% O₂, 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.

中文翻译：

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生长激素 (GH) 在鸡海马细胞培养物中增强氧和葡萄糖剥夺损伤 (OGD) 和复氧 (OGD/R) 后神经保护和神经可塑性的内源性机制

作为经典的生长促进剂和代谢调节剂，生长激素 (GH) 参与中枢神经系统 (CNS) 的发育。这种激素也可能充当神经营养因子，因为 GH 能够在响应神经损伤的修复过程中诱导神经保护、神经突生长和突触发生。缺血性损伤后，神经组织激活由促进组织恢复的局部神经营养因子调节的内源性神经保护机制。在这项工作中，我们研究了 GH 在暴露于缺氧缺血损伤和进一步复氧的培养海马神经元中的神经保护作用。从鸡胚获得的海马细胞培养物在缺氧葡萄糖（OGD，<5% O ₂, 1 g/L 葡萄糖) 条件下 24 小时并同时用 GH 处理。然后，在 GH 存在下，收集细胞进行分析或再氧合和正常葡萄糖孵育条件 (OGD/R) 再处理 24 小时。结果表明，OGD 损伤显着降低了细胞存活率、细胞数量、树突长度和神经突数量，而 OGD/R 阶段恢复了大部分不良反应。此外，OGD/R 增加了几种突触标记物（即 NRXN1、NRXN3、NLG1 和 GAP43）以及生长激素受体 (GHR) 的 mRNA 表达。BDNF、IGF-1 和 BMP4 mRNAs 的表达响应 OGD 损伤而增加，并且暴露于 OGD/R 使其恢复到常氧控制水平，而 NT-3 的表达在两种情况下均增加。在 OGD 期间向海马培养物中添加 GH (10 nM) 可减少细胞凋亡并诱导细胞存活、细胞数量和双皮质素免疫反应性 (DCX-IR) 显着增加，高于在 OGD/R 阶段观察到的结果。GH 处理还保护 OGD 期间的树突和神经突，诱导塑性变化，反映在 OGD/R 期间它们的生长增加和复杂性。此外，GH 增加 OGD 损伤后 NRXN1、NRXN3、NLG1 和 GAP43 的表达。GH 在 OGD 后也增加了 BDNF 的表达，但在 OGD/R 后降低了它。相反，在 OGD/R 后 BMP4 被 GH 上调。总体而言，这些结果表明，神经组织中的 GH 保护作用可以通过其自身作用与由自分泌/旁分泌机制调节的其他局部神经营养因子之间的协同组合来解释，