Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats

Abstract

Sleep disordered breathing (SDB), which is characterized by intermittent hypoxia (IH) during sleep, causes substantial cardiovascular and neurocognitive complications and has become a growing public health problem. SDB is associated with suppression of growth hormone (GH) secretion, the latter being integrally involved in the growth, development and function of the central nervous system (CNS). Since GH treatment is able to attenuate neurocognitive deficits in a hypoxic-ischemic stroke model, GH, GH receptor (GHR) mRNA expression and GH protein expression were assessed in rat hippocampus after exposures to chronic sustained hypoxia (CH, 10% O2) or intermittent hypoxia (IH, 10% O2 alternating with 21% O2 every 90 sec). In addition, the effect of GH treatment (50 µg/kg, daily s.c. injection) on EPO, VEGF, HO-1 and GLUT-1 mRNA expression and neurobehavioral function was assessed. CH significantly increased GH mRNA and protein expression, as well as IGF-1. In contrast, IH only induced a moderate increase in GH mRNA and a slight elevation in GH protein at day 1, but no increases in IGF-1. CH, but not IH, up-regulated GHR mRNA in the hippocampus. IH induced marked neurocognitive deficits compared to CH or room air (RA). Furthermore, exogenous GH administration increased hippocampal mRNA expression of IGF-1, EPO and VEGF, and not only reduced IH-induced hippocampal injury, but also attenuated IH-induced cognitive deficits. Thus, exogenous GH may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from SDB-associated neuronal loss and associated neurocognitive dysfunction.

Growth Hormone Receptors in the Brain and their Potential as Therapeutic Targets in Central Nervous System Disorders

“…Further studies indicated that GH may improve spinal cord conduction and attenuate edema formation and cell injury in the spinal cord provided additional support for a beneficial role of the hormone in injuries to the cord [8,71]. In rats exposed to chronic sustained hypoxia injection of GH increased the hippocampal expression of the IGF-1 gene transcript, reduced the hypoxia-induced hippocampal injury and attenuated hypoxia-induced cognitive deficits [72]. The investigators behind this study concluded that exogenous GH may provide a viable therapeutic intervention to protect hypoxia-vulnerable brain regions from neuronal damage and subsequent deficits in neuro cognitive function.…”

Hypomyelination, memory impairment, and blood–brain barrier permeability in a model of sleep apnea

“…Canessa et al (2011) reported deficits in short-and long-term memories associated with focal reductions in gray matter volume in hippocampus, parietal cortex, and superior frontal gyrus in patients with severe obstructive sleep apnea. Deficits in spatial working memory in water maze protocol were observed in rodents exposed to intermittent hypoxia (Li et al, 2011). However, it has been suggested that a minimum amount of exposition to intermittent hypoxia is necessary to cause detectable memory impairments (Ward et al, 2009).…”

GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats

“…The rhGH treatment in the present study increased the IGF1 gene expression in hippocampus compared with the AAS-treated animals. In alignment with this is a recent demonstration of increased hippocampal Igf1 gene expression in pituitary-intact animals, after GH treatment (Li et al 2011b). Since hippocampus represents a brain area essential for learning and memory it is tempting to suggest that an upregulation of the Igf1 gene transcript in the hippocampus may be associated with improved spatial behavior as seen in the rhGHtreated animals.…”

“…In addition, GH was shown to counteract apoptosis induced by morphine treatment in cells derived from the mouse hippocampus (Svensson et al 2008) and studies have further demonstrated that the hormone may promote neuroprotection (Nyberg & Sharma 2002, Aberg et al 2006. Impairments of spatial learning and memory have also been seen in GH-deficient spontaneous dwarf rats (Li et al 2011a), and in a model with hypoxia GH was able to attenuate deficits in spatial learning (Li et al 2011b). We have recently demonstrated that GH may improve spatial performance in hypophysectomized rats using the Morris water maze (MWM; Le Grevès et al 2006) as well as the radial arm maze (Le Grevès et al 2011).…”