Temporal Changes in Cortical and Hippocampal Expression of Genes Important for Brain Glucose Metabolism Following Controlled Cortical Impact Injury in Mice

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.

Chronic Neurobehavioral Impairments and Decreased Hippocampal Expression of Genes Important for Brain Glucose Utilization in a Mouse Model of Mild TBI

“…In comparison with our previous results in the acute phase of TBI induced by controlled cortical impact (35), the expression of genes encoding glucose or lactose transporters was not affected by mTBI in any of the brain regions measured. Further, expression of genes encoding HK1 and PFK, two of four rate limiting enzymes in glucose metabolism, was not significantly altered in any of the assessed brain regions.…”

“…We previously reported that hippocampal and cortical expression of genes important for brain glucose utilization were all altered by TBI from 6 h to 28 days post brain injury ( 35 ). Those observed temporal alterations in gene expression corresponded closely to temporal alterations in brain glucose utilization reported in TBI patients and experimental animals during the acute and subacute phases of TBI ( 12 – 17 , 47 ).…”

“…Verifications were performed to ensure accuracy of the real-time PCR TaqMan TM method, as we published previously ( 35 ). The detailed real-time PCR TaqMan TM conditions were the same as per the protocol provided by manufacture.…”

Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

“…Additionally, patients with aberrant glucose utilization and network activity during the first week post-TBI have worsened outcomes 6 months later (57). Preclinical work from multiple animal models of TBI shows early increases in glucose utilization (33,(58)(59)(60)(61) which are activity-dependent (34). Consistent with focal hyper-glycolysis and network dysfunction, our previous studies show heightened glutamate signaling in the peri-injury cortex and parvalbumin-interneuron loss also regionally confined to this area.…”

Dysregulated Glucose Metabolism as a Therapeutic Target to Reduce Post-traumatic Epilepsy

“…These changes provide insight into which processes are up- or down-regulated following injury. Examination of the transcriptome after CCI in mice shows increased expression of glycolytic enzymes at 6 h after injury, with later decreases in glycolytic enzyme expression at later time points ( Zhou et al, 2017 ). Similarly, severe FPI in rats resulted in increased expression and enzymatic activity of proteins involved in glycolysis at early time points after injury ( Amorini et al, 2016 ).…”