Changes in cortical and subcortical energy metabolism after repetitive and single controlled cortical impact injury in the mouse.

In the present investigation we examined regional ATP, glucose, and lactate content in the cortical and subcortical region, in a mouse model of controlled cortcal impact (CCI) injury. In serial tissue sections, bioluminescence imaging of ATP, glucose, and lactate was performed 1 h after a single CCI injury or sham surgery and 15 min, 1, 24, and 48 h after the induction of a second CCI injury 24 h later or sham surgery. Bioluminescence images were analyzed by computer-assisted densitometry at the lesion site, at the contralateral site, and in a subcortical region. After repetitive CCI injury, the cortical ATP content decreased bilaterally at 15 min and 1 h, and reached a significant minimum at 24 h, as compared with sham. At 48 h the ATP content bilaterally reached base level again. No significant changes in ATP were found in the subcortical region. After repetitive CCI injury, the lactate content increased bilaterally, reached a significant level at 15 min at the trauma site, and bilaterally reached a significant maximum at 1 h. Thereafter, lactate content decreased below base level without reaching significance and reached baseline again at 48 h. In the ipsilateral subcortical region, lactate content increased transiently above the baseline at 1 h and decreased to a significant minimum at 24 and 48 h. No significant changes were found in the contralateral subcortical area. No significant differences between glucose content in sham animals and the cortical and subcortical area could be measured over time; the subcortical glucose content was bilaterally lower than cortical content at all time points and reached a significant minimum bilaterally at 48 h after repetitive CCI injury compared with cortical glucose content. Single CCI injury did not affect ATP, glucose, and lactate contents at any time point. Repetitive CCI injury caused a more severe depression in cerebral metabolism at early time points after trauma compared with a single CCI injury and indicates that lactate might be an early indicator of post-traumatic metabolic disruption.

Recovery of hepatocellular ATP and "pericentral apoptosis" after hemorrhage and resuscitation.

Progressive liver dysfunction contributes significantly to the development of multiple organ failure after trauma/hemorrhage. This study tested the relative impact of necrotic and apoptotic cell death in a graded model of hemorrhagic shock (mean arterial blood pressure=35+/-5 mmHg for 1, 2, or 3 h, followed by 2 h, 1 h, or no resuscitation, respectively) in rats. Prolonged periods of hemorrhagic hypotension (3 h) were paralleled by a profound decrease of hepatic ATP levels and occurrence of pericentral necrosis. Resuscitation after shorter periods of hemorrhagic hypotension resulted in restoration of tissue ATP whereas hepatocellular function as assessed by indocyanine green clearance remained depressed (49.9+/-1.6 mL/(min x kg) at baseline, 28.8+/-1.2 mL/(min x kg) after 2 h of resuscitation; P<0.05). Under these conditions, induction of caspase activity and DNA fragmentation were observed in pericentral hepatocytes that could be prevented by the radical scavenger tempol. Pretreatment with z-Val-Ala-Asp(O-methyl)-flouromethylketone prevented de novo expression of caspase-generated cytokeratin 18, DNA fragmentation, and depression of hepatocellular indocyanine green clearance. These data suggest that prolonged low flow/hypoxia induces ATP depletion and pericentral necrosis and restoration of oxygen supply and ATP levels after shorter periods of low flow ischemia propagate programmed cell death or "pericentral apoptosis."

Changes in regional energy metabolism after cortical cold lesion in the rat brain.

In the present investigation, regional ATP, glucose, and lactate contents were examined in the cortical and subcortical structures after cold lesion in rats. Bioluminescence imaging of ATP, glucose, and lactate was performed in serial tissue sections at 4 h (n = 4), 12 h (n = 4) and 24 h (n = 4) after cold injury or sham surgery. Bioluminescence images were analyzed by computer-assisted densitometry, at the lesion site, in cortical areas, in the hippocampus, and in the thalamus. ATP and glucose content were significantly decreased at the lesion site as well as on the contralateral side after 4, 12, and 24 h postinjury Lactate content increased significantly in the hippocampal area on the ipsilateral side at 12 h. Cortical lactate was bilaterally unchanged. The cold lesion injury led to a characteristic ischemic profile in the hippocampus signaled by low ATP and glucose content paralleled by high lactate levels. The otherwise global depletion of glucose and ATP suggests that other factors besides cerebral blood flow may contribute to the impairment of energy metabolism.

Regional energy metabolism following short-term neural stem cell transplantation into the injured spinal cord.

Stem cells have been shown to partly restore central nervous system (CNS) function after transplantation into the injured CNS. However, little is known about their influence on acute energy metabolism after spinal cord injury. The present study was designed to analyze regional changes in energy metabolites. Young adult mice were subjected to laminectomy with subsequent hemisection at the L2/3 vertebral level. Immediately thereafter a stable clone of murine neural stem cells (NSCs) was injected into the lesion site. After 4 and 24 h, spinal cords were removed and ATP, glucose, and lactate were analyzed by a bioluminescence approach in serial sections and compared to a laminectomized (intact control), hemisected-only or hemisected vehicle-injected control group. At both time points, ATP content of the hemisected group in the tissue segments adjacent to the lesion was increased when compared to the laminectomized control. At the lesion site ATP content decreased significantly at 24 h in the cell-transplanted group when compared to the laminectomized control group. Glucose content decreased at the lesion site and in segments adjacent to the lesion at both time points and in all experimental groups when compared to the laminectomized control group. Lactate content decreased significantly at 4 h in the caudal segments of the vehicle-injected group and in both adjacent segments of the transplanted group when compared to the laminectomized control. At the lesion site, lactate content decreased significantly at 4 and 24 h in the cell-transplanted group, when compared to the laminectomized control. The area of ATP decline at the lesion site 24 h postinjury was significantly lower in the vehicle control group as compared to the hemisected or transplanted group. The decrease in glucose combined with an increase in ATP in the lesion-adjacent segments may indicate that the tissue responds with an increased use of glucose to support itself with sufficient ATP. The significant decrease in glucose, lactate, and ATP in the cell-transplanted group at 24 h may indicate a high metabolic need of the stem cells. The lower area of ATP decline 24 h after vehicle administration suggests that the vehicle solution washes out toxic mediators, thus ameliorating hemisection-dependent secondary tissue damage.

Stress-resistant neural stem cells positively influence regional energy metabolism after spinal cord injury in mice.

The importance of stem cells to ameliorate the devastating consequences of traumatic injuries in the adult mammalian central nervous system calls for improvements in the capacity of these cells to cope, in particular, with the host response to the injury. We have previously shown, however, that in the acutely traumatized spinal cord local energy metabolism led to decreased ATP levels after neural stem cell (NSC) transplantation. As this might counteract NSC-mediated regenerative processes, we investigated if NSC selected for increased oxidative stress resistance are better suited to preserve local energy content. For this purpose, we exposed wild-type (WT) NSC to hydrogen peroxide prior to transplantation. We demonstrate here that transplantation of WT-NSC into a complete spinal cord compression injury model even lowers the ATP content beyond the level detected in spinal cord injury-control animals. Compared to WT-NSC, stress-resistant (SR) NSC did not lead to a further decrease in ATP content. These differences between WT- and SR-NSC were observed 4 h after the lesion with subsequent transplantation. At 24 h after lesioning, these differences were no more as obvious. Thus, in contrast to native NSC, transplantation of NSC selected for oxidative stress resistance can positively influence local energy metabolism in the first hours after spinal cord compression. The functional relevance of this observation has to be tested in further experiments.