Early and sustained alterations in cerebral metabolism after traumatic brain injury in immature rats

Abstract

Although studies have shown alterations in cerebral metabolism after traumatic brain injury (TBI), clinical data in the developing brain is limited. We hypothesized that post-traumatic metabolic changes occur early (<24 h) and persist for up to 1 week. Immature rats underwent TBI to the left parietal cortex. Brains were removed at 4 h, 24 h, and 7 days after injury, and separated into ipsilateral (injured) and contralateral (control) hemispheres. Proton nuclear magnetic resonance (NMR) spectra were obtained, and spectra were analyzed for N-acetyl-aspartate (NAA), lactate (Lac), creatine (Cr), choline, and alanine, with metabolite ratios determined (NAA/Cr, Lac/Cr). There were no metabolic differences at any time in sham controls between cerebral hemispheres. At 4 and 24 h, there was an increase in Lac/Cr, reflecting increased glycolysis and/or decreased oxidative metabolism. At 24 h and 7 days, there was a decrease in NAA/Cr, indicating loss of neuronal integrity. The NAA/Lac ratio was decreased ( approximately 15-20%) at all times (4 h, 24 h, 7 days) in the injured hemisphere of TBI rats. In conclusion, metabolic derangements begin early (<24 h) after TBI in the immature rat and are sustained for up to 7 days. Evaluation of early metabolic alterations after TBI could identify novel targets for neuroprotection in the developing brain.

FIG. 1.

Representative ¹H spectra from ipsilateral hemisphere (A), contralateral hemisphere (B), or ipsilateral sham control (C) at 24 h after traumatic brain injury (TBI) or sham surgery. The spectra demonstrate good signal-to-noise ratio, with readily measurable peaks for key metabolites. NAA, N-acetyl-aspartate; Lac, lactate; Cr, creatine; Cho, choline; ala, alanine; TMSP, trimethylsilyl proprionate, internal standard.

FIG. 2.

Ipsilateral and contralateral hemispheric ratios of N-acetyl-aspartate to creatine (NAA/Cr) and lactate to creatine (Lac/Cr) at 4 h (A), 24 h (B), and 7 days (C) after traumatic brain injury (TBI). The Lac/Cr ratio was increased ipsilateral to injury at 4 h (A; *p < 0.05 vs. contralateral). At 24 h, the NAA/Cr ratio had decreased and Lac/Cr remained increased ipsilateral to injury (B; *p < 0.05 vs. contralateral). By 7 days, the ipsilateral NAA/Cr remained decreased (C; *p < 0.05 vs. contralateral).

FIG. 3.

The N-acetyl-aspartate to lactate (NAA/Lac) ratio was decreased ipsilateral to injury at all time points studied in injured rats (4 h, 24 h, and 7 days; all *p < 0.05 ipsilateral vs. contralateral).

FIG. 4.

Full time-course plots of the trends in metabolic ratios of N-acetyl-aspartate to creatine (NAA/Cr; A), lactate to creatine (Lac/Cr; B), and N-acetyl-aspartate to lactate (NAA/Lac; C) in traumatic brain injury (TBI; solid lines) and sham (dashed lines) rats, with ipsilateral samples represented by closed marks and contralateral with open marks (*p < 0.05 TBI ipsilateral vs. contralateral). Both the Naa/Cr and Lac/Cr ratios were lower at 1 week than at 4 or 24 h in TBI ipsilateral samples (^πp < 0.05 1 week vs. 4 and 24 h). The NAA/Lac ratio was higher at 1 week than at 24 h in TBI ipsilateral samples (^δp < 0.05 1 week vs. 24 h).

FIG. 5.

Time-course plot of the choline to creatine (Cho/Cr) ratio in traumatic brain injury (TBI; solid lines) and sham (dashed lines) rats, with ipsilateral samples represented by closed marks and contralateral with open marks. There was a significant increase in the Cho/Cr ratio at 7 days in TBI rats ipsilateral to injury (*p < 0.05 vs. TBI contralateral).