Diminution of metabolism/blood flow uncoupling following traumatic brain injury in rats in response to high-dose human albumin treatment.

OBJECT: The authors have recently demonstrated that high-dose human albumin is markedly neuroprotective in experimental traumatic brain injury (TBI) and cerebral ischemia. The pathophysiology of TBI involves acute uncoupling of cerebral glucose utilization and blood flow. The intent of this study was to establish whether the use of human albumin therapy in a model of acute TBI would influence this phenomenon. METHODS: Anesthetized, physiologically regulated rats received moderate (1.5-2 atm) fluid-percussion injury to the parietal lobe. Fifteen minutes after trauma or sham injury, rats in one group received human albumin (2.5 g/kg) administered intravenously and those in another group received 0.9% saline vehicle. At 60 minutes and 24 hours posttrauma, autoradiographic studies of local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) were conducted, and the LCMRglu/LCBF ratio was determined. Sham-injured rats had normal levels of LCBF and LCMRglu, and no differences between vehicle- and albumin-treated rats were evident. Sixty minutes after TBI, LCBF was moderately reduced bilaterally in vehicle-treated rats, whereas in albumin-treated animals, the LCBF contralateral to the side of injury was generally normal. Despite acutely depressed LCBF, LCMRglu in vehicle-treated rats at 60 minutes was paradoxically normal bilaterally, and foci of elevated LCMRglu were noted in the ipsilateral hippocampus and thalamus. By contrast, in albumin-treated rats studied 60 minutes post-TBI, reduced LCMRglu values were measured in the ipsilateral caudoputamen and parietal cortex, whereas LCMRglu in other ipsilateral and contralateral sites did not differ from that measured in sham-injured animals. The metabolism/blood flow ratio was normal in sham-injured rats, but became markedly elevated in vehicle-treated rats 60 minutes post-TBI (on average, by threefold ipsilaterally and 2.1-fold contralaterally). By contrast, the mean metabolism/blood flow ratio in albumin-treated animals was elevated by only 1.6-fold ipsilaterally and was normal contralaterally. Twenty-four hours after TBI, LCBF contralateral to the side of injury had generally returned to normal levels in the albumin-treated group. CONCLUSIONS: These results demonstrate that human albumin therapy benefits the posttraumatic brain by diminishing the pronounced metabolism > blood flow dissociation that would otherwise occur within the 1st hour after injury. Viewed together with our previous evidence of histological neuroprotection, these findings indicate that human albumin therapy may represent a desirable treatment modality for acute TBI.

Chronic metabolic sequelae of traumatic brain injury: prolonged suppression of somatosensory activation.

Injuries to the brain acutely disrupt normal metabolic function and may deactivate functional circuits. It is unknown whether these metabolic abnormalities improve over time. We used 2-deoxyglucose (2-DG) autoradiographic image-averaging to assess local cerebral glucose utilization (lCMR(Glc)) of the rat brain 2 mo after moderate (1.7-2.1 atm) fluid-percussion traumatic brain injury (FPI). Four animal groups (n = 5 each) were studied: sham-injured rats with and without stimulation of the vibrissae-barrel field ipsilateral to injury; and animals with prior FPI, with or without this stimulation. In sham-injured rats, resting lCMR(Glc) was normal, and vibrissae stimulation produced right-sided metabolic activation of the ventrolateral thalamic and somatosensory-cortical projection areas. In rats with prior injury, lCMR(Glc) contralateral to injury was normal, but lCMR(Glc) of the ipsilateral forebrain was depressed by approximately 38-45% compared with shams. Whisker stimulation in rats with prior trauma failed to induce metabolic activation of either cortex or thalamus. Image-mapping of histological material obtained in the same injury model was undertaken to assess the possible influence of injury-induced regional brain atrophy on computed lCMR(Glc); an effect was found only in the lateral cortex at the trauma epicenter. Our results show that, 2 mo after trauma, resting cerebral metabolic perturbations persist, and the whisker-barrel somatosensory circuit shows no signs of functional recovery.

Expression of brain-derived neurotrophic factor, nerve growth factor, and heat shock protein HSP70 following fluid percussion brain injury in rats.

Traumatic brain injury can induce the expression of stress-related and neurotrophic genes both within the injury site and in distant regions. These genes may affect severity of damage and/or be neuroprotective. We used in situ hybridization to assess the alterations in expression of the heat shock protein HSP70, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) genes in rat brain following moderate fluid-percussion (F-P) injury at various survival times. HSP70 gene expression was induced at and surrounding the injury site as early as 30 min after trauma. This elevated signal spread ventrally and laterally through the ipsilateral cortex and into the underlying white matter over the next few hours. In addition, there was elevated expression in the temporal hippocampus. BDNF was strongly upregulated in the granular cells of the dentate gyrus and in the CA3 hippocampus 2-6 h after injury. Cortical regions at and near the injury site showed no response at the mRNA level. NGF mRNA increased over the granular cells of the dentate gyrus at early time points. There was also a weaker secondary induction of the NGF gene in the contralateral dentate gyrus of some animals. Cortical response was observed in the entorhinal cortex, bilaterally, but not at the injury site. All three of the studied genes responded quickly to injury, as early as 30 min. The induction of gene expression for neurotrophins in regions remote from areas with histopathology may reflect coupling of gene expression to neuronal excitation, which may be associated with neuroprotection and plasticity.

Influence of early posttraumatic hypothermia therapy on local cerebral blood flow and glucose metabolism after fluid-percussion brain injury.

OBJECT: Using autoradiographic image averaging, the authors recently described prominent foci of marked glucose metabolism-greater-than-blood-flow uncoupling in the acutely traumatized rat brain. Because hypothermia is known to ameliorate injury in this and other injury models, the authors designed the present study to assess the effects of posttraumatic therapeutic hypothermia on the local cerebral metabolic rate of glucose (LCMRglu) and local cerebral blood flow (LCBF) following moderate parasagittal fluid-percussion head injury (FPI) in rats. METHODS: Either cranial hypothermia (30 degrees C) or normothermia (37 degrees C) was induced for 3 hours in matched groups of rats immediately after FPI; LCMRglu and LCBF were assessed 3 hours after concluding these temperature manipulations. In rats subjected to FPI, regardless of whether normothermia or hypothermia ensued, LCBF was reduced relative to the sham-injury groups. In addition, when FPI was followed by hypothermia (FPI-30 degrees C group), the subsequent LCBF was significantly lower (35-38% on average) than in FPI-37 degrees C rats. Statistical mapping of LCBF difference imaging data revealed confluent cortical and subcortical zones of significantly reduced LCBF (largely ipsilateral to the prior injury) in FPI-30 degrees C rats relative to the FPI-37 degrees C group. Local glucose utilization was reduced in both hemispheres of FPI-37 degrees C rats relative to the sham-injury group and was lower in the right (traumatized) hemisphere than in the left. However, LCMRglu values were largely unaffected by temperature manipulation in either the FPI or sham-injury groups. The LCMRglu/LCBF ratio was nearly doubled in FPI-30 degrees C rats relative to the FPI-37 degrees C group, in a diffuse and bihemispheric fashion. Linear regression analysis comparing LCMRglu and LCBF revealed that the FPI-37 degrees C and FPI-30 degrees C data sets were completely nonoverlapping, whereas the two sham-injury data sets were intermixed. CONCLUSIONS: Despite its proven neuroprotective efficacy, early posttraumatic hypothermia (30 degrees C for 3 hours) nonetheless induces a moderate decline in cerebral perfusion without the (anticipated) improvement in cerebral glucose utilization, so that a state of mild metabolism-greater-than-blood-flow dissociation is perpetuated.

Local cerebral glucose utilization and cytoskeletal proteolysis as indices of evolving focal ischemic injury in core and penumbra.

To ascertain the tempo of progression to irreversible injury in focal ischemia, we subjected halothane-anesthetized Sprague-Dawley rats to photochemically induced distal middle cerebral artery occlusion (dMCAO) combined with permanent ipsilateral and 1 h contralateral common carotid artery occlusions. Head temperature was maintained at 36 degrees C. At times centered at either 1.5 or 3 h post-dMCAO, the rate of local glucose metabolism (lCMRgl) was measured by 2-deoxyglucose autoradiography, and cytoskeletal proteolysis was assessed regionally by an immunoblotting procedure to detect spectrin breakdown products. At 1.5 h (n = 5), the cortical ischemic core was already severely hypometabolic (lCMRgl 15.5 +/- 10.8 mumol 100 g-1 min-1, mean +/- SD), whereas the cortical penumbral zone was hypermetabolic (69.0 +/- 9.7). (The lumped constant was verified to be unchanged by methylglucose studies). Neutral red pH studies at this time point showed that both the core and penumbral zones were equally acidotic. By 3 h post-dMCAO (n = 6), lCMRgl in the penumbral zone had fallen to low levels (15.4 +/- 2.2 mumol 100 g-1 min-1) equal to those of the ischemic core (16.7 +/- 4.5). Correspondingly, spectrin breakdown in the ischemic core was advanced at both 2 and 3.5 h post-dMCAO (36 +/- 18% and 33 +/- 18% of total spectrin, respectively), whereas in the penumbral zone spectrin breakdown was less extensive and more highly variable at both times (22 +/- 23% and 29 +/- 16%). We conclude that irreversible deterioration of the ischemic core, as evidenced by the onset of local cytoskeletal proteolysis, begins within 2 h of middle cerebral artery occlusion. In the ischemic penumbra, the transition from glucose hyper- to hypometabolism occurs by 3.5 h and is associated with a milder and more variable degree of spectrin breakdown.