Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-OHDG, and increases in HIF-1α DNA binding and up-regulation of IGF-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction.

睡眠期间的间歇性缺氧（IH），比如在阻塞性睡眠呼吸暂停（OSA）中出现的情况，会导致海马体的退行性变化，并且与成年小鼠的空间学习能力缺陷有关。在OSA患者和小鼠模型中，该疾病都与生长激素（GH）分泌受抑制有关，而生长激素积极参与中枢神经系统（CNS）的生长、发育和功能。近期的研究表明，外源性生长激素疗法可减轻大鼠睡眠期间由间歇性缺氧引发的神经认知缺陷。在此我们发现，给予生长激素释放激素（GHRH）激动剂JI - 34可减轻小鼠由间歇性缺氧诱导的神经认知缺陷、焦虑和抑郁，同时降低丙二醛（MDA）和8 - 羟基脱氧鸟苷（8 - OHDG）等氧化应激标志物，并增加缺氧诱导因子 - 1α（HIF - 1α）的DNA结合以及胰岛素样生长因子 - 1（IGF - 1）和促红细胞生成素表达的上调。相比之下，在间歇性缺氧期间使用生长激素释放激素拮抗剂（MIA - 602）进行治疗，对小鼠由间歇性缺氧诱导的任何有害影响都没有作用。因此，以外源性生长激素释放激素激动剂的配方给药，可能为保护易受间歇性缺氧影响的大脑区域免受阻塞性睡眠呼吸暂停相关的神经认知功能障碍提供一种可行的治疗干预措施。