The metabolic fate of [1,2 13C]-labeled glucose was determined in male control and unilateral controlled cortical impact (CCI) injured rats at 3.5 and 24 h after surgery. The concentration of 13C-labeled glucose, lactate, glutamate and glutamine were measured in the injured and contralateral cortex. CCI animals showed a 145% increase in 13C lactate in the injured cortex at 3.5 h, but not at 24 h after injury, indicating increased glycolysis in neurons and/or astrocytes ipsilateral to CCI. Total levels of 13C glutamate in cortical tissue extracts did not differ between groups. However, 13C glutamine increased by 40% in the left and 98% in the right cortex at 3.5 h after injury, most likely resulting from an increase in astrocytic metabolism of glutamate. Levels of 13C incorporation into the glutamine isotopomers had returned to control levels by 24 h after CCI. The singlet to doublet ratio of the lactate C3 resonances was calculated to estimate the flux of glucose through the pentose phosphate pathway (PPP). CCI resulted in bilateral increases (9-12%) in the oxidation of glucose via the PPP, with the largest increase occurring at 24 h. Since an increase in PPP activity is associated with NADPH generation, the data suggest that there was an increasing need for reducing equivalents after CCI. Furthermore, 13C was incorporated into glutamate and glutamine isotopomers associated with multiple turns of the tricarboxylic acid (TCA) cycle, indicating that oxidative phosphorylation of glucose was maintained in the injured cortex at 3.5 and 24 h after a moderate to severe CCI injury.

Cerebrovascular disruption and cortical pathology resulting from either moderate (M-TBI) or severe (S-TBI) traumatic brain injury produced by a pneumatically-driven cortical contusion device were assessed in adult male rats sacrificed at 6 and 24 h or 8 and 30 days after injury to the right sensorimotor cortex. Epidural, subdural, subarachnoid, petechial (cortex and corpus callosum), and/or intraventricular hemorrhage was present in all animals, more extensively and severely following S-TBI. At 6 or 24 h after TBI, acidophilic (acid fuchsin-positive) neurons were numerous and widespread (S-TBI > M-TBI) in the ipsilateral contused cortex. By 8 days few acidophilic neurons were present in peri-impact regions of the ipsilateral neocortex, and none were detected in cortex 30 days postinjury. Both M-TBI and S-TBI groups had enlarged ipsilateral cortical volumes (edema) at 6 and 24 h post-contusion. Eight and 30 days after injury the mean volume of cortical necrosis was significantly larger in S-TBI than in M-TBI rats, and cortical necrosis in both TBI conditions increased between 8 to 30 days postinjury. These results indicate that this pneumatically-driven contusion device produces reliable and consistent primary and secondary cortical histopathology, the extent of which is related to the severity of initial injury.

The increased CMRO2 and decreased CSF lactate levels after treatment indicate that HBO may improve aerobic metabolism in severely brain injured patients. This is the first study to demonstrate a prolonged effect of HBO treatment on CBF and cerebral metabolism. On the basis of their data the authors assert that shorter, more frequent exposure to HBO may optimize treatment.

No abstract

This study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MD glc ), lactate (MD lac ), and pyruvate (MD pyr ), and the effects of SP treatment on neuropathology after left cortical contusion injury (CCI) in rats. SP injection (1000 mg=kg) 5 min after sham injury (Sham-SP) or CCI (CCI-SP) significantly increased arterial pyruvate ( p < 0.005) and lactate ( p < 0.001) compared to that of saline-treated rats with CCI (CCI-Sal). Serum glucose also increased significantly in CCI-SP compared to that in CCI-Sal rats ( p < 0.05), but not in Sham-SP rats. MD pyr was not altered after CCI-Sal, whereas MD lac levels within the cerebral cortex significantly increased bilaterally ( p < 0.05) and those for MD glc decreased bilaterally ( p < 0.05). MD pyr levels increased significantly in both Sham-SP and CCI-SP rats ( p < 0.05 vs. CCI-Sal) and were higher in left=injured cortex of the CCI-SP group ( p < 0.05 vs. sham-SP). In CCI-SP rats the contralateral MD lac decreased below CCI-Sal levels ( p < 0.05) and the ipsilateral MD glc levels exceeded those of CCI-Sal rats ( p < 0.05). Rats with a single low (500 mg=kg) or high dose (1000 mg=kg) SP treatment had fewer damaged cortical cells 6 h post-CCI than did saline-treated rats ( p < 0.05), but three hourly injections of SP (1000 mg=kg) were needed to significantly reduce contusion volume 2 weeks after CCI. Thus, a single intraperitoneal SP treatment increases circulating levels of three potential brain fuels, attenuates a CCI-induced reduction in extracellular glucose while increasing extracellular levels of pyruvate, but not lactate, and can attenuate cortical cell damage occurring within 6 h of injury. Enduring (2 week) neuronal protection was achieved only with multiple SP treatments within the first 2 h post-CCI, perhaps reflecting the need for additional fuel throughout the acute period of increased metabolic demands induced by CCI.

The current dogma to explain the extent of injury related changes following rodent controlled cortical impact (CCI) injury is a focal injury with limited axonal pathology. However, there is in fact good, published histologic evidence to suggest that axonal injury is far more widespread in this model than generally thought. One possibility that might help to explain this is the often-used region-of-interest data analysis approach taken by experimental traumatic brain injury (TBI) diffusion tensor imaging (DTI) or histologic studies that might miss more widespread damage, when compared to the whole brain, statistically robust method of tract based analysis used more routinely in clinical research. To determine the extent of DTI changes in this model, we acquired in vivo DTI data before and at 1 and 4 weeks after CCI injury in 17 adult, male rats and analyzed parametric maps of fractional anisotropy (FA), axial, radial and mean diffusivity (AD, RD, MD), tensor mode (MO), and fiber tract density (FTD) using tract based spatial statistics. Contusion volume was used as a surrogate marker of injury severity and as a covariate for investigating severity dependence of the data. Mean fiber tract length was also computed from seeds in the cortical spinal tract regions. In parallel experiments (n=3–5/group) we investigated corpus callosum neurofilaments and demyelination using immunohistochemistry (IHC) at 3 days and 6 weeks, callosal tract patency using dual-label retrograde tract-tracing at 5 weeks, and the contribution of gliosis to DTI parameter maps using GFAP IHC at 4 weeks post-injury. The data show widespread ipsilateral regions of significantly reduced FA at 1 week post-injury, driven by temporally changing values of AD, RD and MD that persist to 4 weeks. Demyelination, retrograde label tract loss, and reductions in MO (tract degeneration) and FTD were shown to underpin these data. Significant FA increases occurred in subcortical and corticospinal tract regions that were spatially distinct from regions of FA decrease, grossly affected gliotic areas and from MO changes. However, there was good spatial correspondence between regions of increased FA and areas of increased FTD and mean fiber length. We discuss these widespread changes in DTI parameters in terms of axonal degeneration and potential reorganization, with reference to a resting state fMRI companion paper (Harris et al, 2016, Exp. Neurol.227:124–138) that demonstrated altered functional connectivity data acquired from the same rats used in this study.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

Cognitive deficits are the most enduring and disabling sequelae of human traumatic brain injury (TBI), but quantifying the magnitude, duration, and pattern of cognitive deficits produced by different types of TBI has received little emphasis in preclinical animal models. The objective of the present study was to use a battery of behavioral tests to determine if different impact sites produce different patterns of behavioral deficits and to determine how long behavioral deficits can be detected after TBI. Prior to surgery, rats were trained to criteria on delayed nonmatching to position, radial arm maze, and rotarod tasks. Rats received sham surgery (controls), midline frontal contusions (frontal TBI, 2.25 m/sec impact), or unilateral sensorimotor cortex contusions (lateral TBI, 3.22 m/sec impact) at 12 months of age and were tested throughout the next 12 months. Cognitive deficits were more robust and more enduring than sensorimotor deficits for both lateral TBI and frontal TBI groups. Lateral TBI rats exhibited transient deficits in the forelimb placing and in the rotarod test of motor/ambulatory function, but cognitive deficits were apparent throughout the 12-month postsurgery period on tests of spatial learning and memory including: (1)reacquisition of a working memory version of the radial arm maze 6-7 months post-TBI, (2) performance in water maze probe trials 8 months post-TBI, and (3) repeated acquisition of the Morris water maze 8 and 11 months post-TBI. Frontal TBI rats exhibited a different pattern of deficits, with the most robust deficits in tests of attention/orientation such as: (1) the delayed nonmatching to position task (even with no delays) 1-11 weeks post-TBI, (2) the repeated acquisition version of the water maze--especially on the first "information" trial 8 months post-TBI, (3) a test of sensorimotor neglect or inattention 8.5 months post-TBI, and (4) a DRL20 test of timing and/or sustained attention 11 months after surgery. These results suggest that long-term behavioral deficits can be detected in rodent models of TBI, that cognitive deficits seem to be more robust than sensorimotor deficits, and that different TBI impact sites produce dissociable patterns of cognitive deficits in rats.