Abstract
Traumatic brain injury (TBI) causes transient increases and subsequent decreases in brain glucose utilization. The underlying molecular pathways are orchestrated processes and poorly understood. In the current study, we determined temporal changes in cortical and hippocampal expression of genes important for brain glucose/lactate metabolism and the effect of a known neuroprotective drug telmisartan on the expression of these genes after experimental TBI. Adult male C57BL/6J mice (n = 6/group) underwent sham or unilateral controlled cortical impact (CCI) injury. Their ipsilateral and contralateral cortex and hippocampus were collected 6 h, 1, 3, 7, 14, 21, and 28 days after injury. Expressions of several genes important for brain glucose utilization were determined by qRT-PCR. In results, (1) mRNA levels of three key enzymes in glucose metabolism [hexo kinase (HK) 1, pyruvate kinase, and pyruvate dehydrogenase (PDH)] were all increased 6 h after injury in the contralateral cortex, followed by decreases at subsequent times in the ipsilateral cortex and hippocampus; (2) capillary glucose transporter Glut-1 mRNA increased, while neuronal glucose transporter Glut-3 mRNA decreased, at various times in the ipsilateral cortex and hippocampus; (3) astrocyte lactate transporter MCT-1 mRNA increased, whereas neuronal lactate transporter MCT-2 mRNA decreased in the ipsilateral cortex and hippocampus; (4) HK2 (an isoform of hexokinase) expression increased at all time points in the ipsilateral cortex and hippocampus. GPR81 (lactate receptor) mRNA increased at various time points in the ipsilateral cortex and hippocampus. These temporal alterations in gene expression corresponded closely to the patterns of impaired brain glucose utilization reported in both TBI patients and experimental TBI rodents. The observed changes in hippocampal gene expression were delayed and prolonged, when compared with those in the cortex. The patterns of alterations were specific to different brain regions and exhibited different recovery periods following TBI. Oral administration of telmisartan (1 mg/kg, for 7 days, n = 10 per group) ameliorated cortical or hippocampal mRNA for Glut-1/3, MCT-1/2 and PDH in CCI mice. These data provide molecular evidence for dynamic alteration of multiple critical factors in brain glucose metabolism post-TBI and can inform further research for treating brain metabolic disorders post-TBI.
Highlights
Glucose is an essential fuel for maintaining cellular functions
Considering pleiotropic actions of telmisartan on traumatic brain injury (TBI) and glucose metabolism, we examined its effects on expression of genes that regulate to brain glucose utilization in a TBI mouse model
Hexokinase 1, pyruvate kinase (PK), and pyruvate dehydrogenase (PDH) are three rate-limiting enzymes that play critical roles in glucose metabolism (Figures 1 and 2). mRNA expressions of all three of these enzymes were significantly altered after cortical impact (CCI) (Figure 2)
Summary
Glucose is an essential fuel for maintaining cellular functions. Secondary injury elicits a series of pathophysiological cascade, including edema, increased intracranial pressure, hemorrhage, and decreased cerebral blood flow. Cellular processes during the secondary injury phase involve excessive release of excitatory neurotransmitters, activation of ion channels, mitochondrial dysfunction, hypoxia, and inflammation [1, 2], all leading to degradation of cellular structures, apoptosis [3], and affecting brain glucose requirements and utilization [4, 5]. TBI consistently triggers transient increases and prolonged decreases in brain glucose utilization, as assessed by brain imaging in both TBI patients and experimental animals [6,7,8,9,10,11,12]
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