Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1α and its downstream target genes

Abstract

Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1alpha. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O(2) at 37 degrees C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1alpha was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1alpha and p53 was also examined. An elevated expression of HIF-1alpha, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1alpha was followed by an increase in the association of HIF-1alpha with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1alpha and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1alpha-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1alpha phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.

HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic–ischemic model

“…Our previous studies as well as others have shown that HIF-1α protein levels increased and peaked at 3-4 hr after hypoxic-ischemic injury (Calvert et al, 2006;van den Tweel et al, 2006), at 7.5 hrs after focal cerebral ischemia in adults and at 96 hrs in adult global ischemic model (Jin et al, 2000;Li et al, 2005). The ineffectiveness of 2ME2 when administered at 3 h after HI in the present study strongly suggested that neuroprotective effects are dependent on early HIF-1α inhibition i.e.…”

“…A modified Rice-Vannucci model (Rice et al, 1981) was adopted as follows (Calvert et al, 2006): 7-day-old postnatal pups were anesthetized with isoflurane (3% in a mixture of medical air and oxygen 70:30 ratio). The right common carotid artery of each pup was identified, exposed, and permanently ligated with 5-0 surgical silk through a near-midline incision.…”

Increased expression of glucose transporter 3 in gerbil brains following magnesium sulfate treatment and focal cerebral ischemic injury

“…3,[9][10][11] In neurons, phosphorylated cyclic AMP-regulatory element-binding (pCREB) protein and the mouse Y box-binding protein-1 (MSY-1) bind the Glut3 12 Phosphorylation of CREB has been linked to neuroprotection both in vitro and in vivo ischemia models. 13,14 CREB is phosphorylated using multiple kinases including protein kinase A (PKA), calcium-calmodulin kinases (CaMK), protein kinase B (PKB), protein kinas C (PKC), and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK, MEK).…”

The effect of hyperbaric oxygen on neuroregeneration following acute thoracic spinal cord injury

“…A reduction in spinal cord tissue cystic necrosis and damage in the surrounding white matter following HBO treatment was also observed by Yeo et al (1977). HBO reduced apoptosis following SCI (Calvert et al 2006, Peng et al 2008, Wang et al 2009). Higgins et al (1981) studied spinal cord electropotentials and showed that early HBO treatment contributed to the prevention of progressive degeneration in SCI.…”