Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Unidad Predepartamental de Medicina, Universidad Jaume I, Castellón, Spain.
Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
Neuroscience. 2018 Mar 15;374:104-118. doi: 10.1016/j.neuroscience.2018.01.041. Epub 2018 Feb 3.
Somatostatin (SRIF), a neuropeptide highly distributed in the hippocampus and involved in learning and memory, is markedly reduced in the brain of Alzheimer's disease patients. The effects of insulin-like growth factor-I (IGF-I) against β amyloid (Aβ)-induced neuronal death and associated cognitive disorders have been extensively reported in experimental models of this disease. Here, we examined the effect of IGF-I on the hippocampal somatostatinergic system in Aβ-treated rats and the molecular mechanisms associated with changes in this peptidergic system. Intracerebroventricular Aβ25-35 administration during 14 days (300 pmol/day) to male rats increased Aβ25-35 levels and cell death and markedly reduced SRIF and SRIF receptor 2 levels in the hippocampus. These deleterious effects were associated with reduced Akt and cAMP response element-binding protein (CREB) phosphorylation and activation of c-Jun N-terminal kinase (JNK). Subcutaneous IGF-I co-administration (50 µg/kg/day) reduced hippocampal Aβ25-35 levels, cell death and JNK activation. In addition, IGF-I prevented the reduction in the components of the somatostatinergic system affected by Aβ infusion. Its co-administration also augmented protein kinase A (PKA) activity, as well as Akt and CREB phosphorylation. These results suggest that IGF-I co-administration may have protective effects on the hippocampal somatostatinergic system against Aβ insult through up-regulation of PKA activity and Akt and CREB phosphorylation.
生长抑素（SRIF）是一种在海马体中高度分布的神经肽，参与学习和记忆，在阿尔茨海默病患者的大脑中明显减少。胰岛素样生长因子-I（IGF-I）对β淀粉样蛋白（Aβ）诱导的神经元死亡和相关认知障碍的作用在这种疾病的实验模型中得到了广泛的报道。在这里，我们研究了 IGF-I 对 Aβ 处理大鼠海马生长抑素能系统的影响，以及与这种肽能系统变化相关的分子机制。在雄性大鼠中，14 天（300 pmol/天）脑室内给予 Aβ25-35 可增加 Aβ25-35 水平和细胞死亡，并显著降低海马中的生长抑素和生长抑素受体 2 水平。这些有害影响与 Akt 和 cAMP 反应元件结合蛋白（CREB）磷酸化和 c-Jun N-末端激酶（JNK）激活减少有关。皮下 IGF-I 共同给药（50 µg/kg/天）可降低海马 Aβ25-35 水平、细胞死亡和 JNK 激活。此外，IGF-I 可防止 Aβ 输注对生长抑素能系统成分的减少。其共同给药还增强了蛋白激酶 A（PKA）活性以及 Akt 和 CREB 磷酸化。这些结果表明，IGF-I 共同给药可能通过上调 PKA 活性和 Akt 和 CREB 磷酸化对 Aβ 损伤的海马生长抑素能系统具有保护作用。
