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

Abstract

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.

Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice

“…IH is the main feature of OSA (Kohler and Stradling, 2010;Nair et al, 2013;Quintero et al, 2013), leading to injuries to a variety of organs and systems (Gami et al, 2004;Kendzerska et al, 2014;Marin et al, 2012;Nicholl et al, 2012;Peppard et al, 2000;Redline et al, 2010;Sakaguchi et al, 2011;Tan et al, 2014). Accumulating clinical evidences have indicated that OSA is an independent risk factor for loss of kidney function (Ahmed et al, 2011;Chou et al, 2011;Nicholl et al, 2012).…”

“…However, how IH impairs kidney remains unclear. IH is believed to induce oxidative stress (Chen et al, 2014;Nair et al, 2013;Quintero et al, 2013) which contributes to renal injury (Zheng et al, 2011). MT has been defined as a potent antioxidant that effectively protects kidney from oxidative damage (Kojima et al, 2009;Shimazu et al, 2013;Sun et al, 2014b).…”

“…IH is believed to induce oxidative stress (Chen et al, 2014;Nair et al, 2013;Quintero et al, 2013) which contributes to renal injury (Zheng et al, 2011). Consequently, MDA as an index of lipid peroxidation in response to oxidative stress was measured and showed that contents of renal MDA was significantly increased in both WT and MT KO mice at all four time points except 1 week after IH exposure in WT mice, which were further aggravated by MT deletion (Fig.…”

“…As a critical feature of OSA, IH causes oxidative stress (Kohler and Stradling, 2010;Nair et al, 2013;Quintero et al, 2013), leading to injuries to a variety of organs, including kidney. Oxidative stress is defined as an imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage (Sheng et al, 2014).…”

The polymorphic and contradictory aspects of intermittent hypoxia

“…Although continuous hypoxia promotes the increased expression and activity of both molecules (71), acute IH upregulates HIF-1␣ and downregulates HIF-2␣ protein via calpains (125). Furthermore, contrary to sustained hypoxia, long-term IH during sleep has been reported to induce early activation of HIF-1␣ in the brain that is then followed by reductions in HIF-1␣ expression or its target genes over time (41,99,122). If we consider that HIF-2␣ regulates the transcription of several antioxidant enzymes including SOD-2 (169), the downregulation of HIF-2␣ in the context of acute IH may also contribute to increases in ROS via insufficient transcription of antioxidative enzymes.…”