Abstract
Hypoxia preconditioning (HPC), a well-established preconditioning model, has been shown to protect the brain against severe hypoxia or ischemia caused by traumatic brain injury (TBI), but the mechanism has not been well elucidated. Anaerobic glycolysis is the major way for neurons to produce energy under cerebral ischemia and hypoxia after TBI, and it requires large amounts of glucose. We hypothesized that glucose transport, as a rate-limiting step of glucose metabolism, may play key roles in the neuroprotective effects of HPC on cerebral cortex tissue against TBI. The aim of this study was to investigate the effect of HPC on glucose transport activity of rat cerebral cortex tissue after TBI through examining the gene expression of two major glucose transporters (GLUT1 and GLUT3) and their upstream target gene hypoxia-inducible factor-1α (HIF-1α). Sprague-Dawley rats were treated with HPC (50.47 kPa, 3 h/d, 3d). Twenty-four hours after the last treatment, the rats were injured using the Feeney free falling model. Cortex tissues of injured rats were removed at 1 h, 4 h, 8 h, 12 h, 1 day, 3 days, 7 d, and 14 days post-injury for histological analysis. Compared with TBI alone, HPC before TBI resulted in the expression of HIF-1α, GLUT1, and GLUT3 to increase at 1 h; they were markedly increased at 4 h, 8 h, 12 h, 1 day, and 3 days and decreased thereafter (p < 0.05). HPC before TBI could improve neuronal survival in rats by examining NeuN staining and observing reduced apoptosis by examining TUNEL staining. The result showed that HPC before TBI could increase the expression of GLUT1 and GLUT3. And through double immunofluorescence staining for GLUT3 and NeuN, the results strongly suggest that HPC improved glucose transport activity of neurons in rats with TBI. In summary, our results further support that HPC can improve hypoxia tolerance and attenuate neuronal loss of cerebral cortex in rats after TBI. The mechanism is mainly related to the increase of glucose transport activity through inducing GLUT1 and GLUT3 expression through upregulating HIF-1α expression.
Highlights
In recent years, many studies have shown that hypoxia preconditioning (HPC) could increase the resistance of brain to subsequent hypoxic insults [1,2,3]
We previously demonstrated in vivo that cerebral hypoxiaischemia caused by traumatic brain injury (TBI) plays a crucial role in producing a variety of severe secondary brain damage [10,11,12]
Because only glucose can be used by neurons under anaerobic conditions, increased hypoxia-inducible factor-1α (HIF-1α) expression under hypoxia will increase the expression of GLUT1 and GLUT3 to provide supplementary glucose for glycolysis [23,24,25]
Summary
Many studies have shown that hypoxia preconditioning (HPC) could increase the resistance of brain to subsequent hypoxic insults [1,2,3]. Cerebral hypoxia-ischemia after TBI reduces oxygen delivery and leads to disordered glucose metabolism [13, 14]. The role of GLUT1 is mainly to transport glucose across the endothelial cells of the blood-brain barrier (BBB) and help glucose pass through the glial cell membrane [7]. GLUT3 mainly helps glucose to pass through the neuronal cell membrane [18]. GLUT1 and GLUT3 levels in brain tissue are increased after TBI, strongly suggesting that inhibiting the function of GLUTs leads to abnormal brain function and neuronal death [19]. Studies using different methodologies showed increased glucose metabolism in the affected brain after TBI [20,21,22]. Because only glucose can be used by neurons under anaerobic conditions, increased HIF-1α expression under hypoxia will increase the expression of GLUT1 and GLUT3 to provide supplementary glucose for glycolysis [23,24,25]
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