Search

AbstractTraumatic brain injury (TBI) results in enduring functional deficits. Strategies aimed at promoting plasticity within the injured brain may aid in enhancing functional outcome. We have previously shown that spontaneous pericontusional axon sprouting occurs within 7–14 days after controlled cortical impact injury in the adult rat, but ultimately fails due to an increasingly growth-inhibitory environment. We therefore sought to determine whether acute infusion of chondroitinase ABC into the site of the cortical contusion, to further reduce pericontusional growth-inhibitory chondroitin sulfate proteoglycans (CSPGs), would enhance and prolong the sprouting response. We also wanted to determine if chondroitinase-enhanced sprouting would ameliorate the behavioral deficits in forelimb function that occur in this model. Acute chondroitinase infusion decreased intact CSPGs and significantly increased pericontusional cortical grey and white matter growth-associated protein 43 (GAP43)-positive axon sprouting at 7 days post-injury. A return of intact CSPGs at later time points likely contributed to the absence of persistently increased levels of axon sprouting by 14–21 days post-injury. There was no overall benefit on forelimb function during the time of maximal sprouting or at any subsequent times in three of four behavioral outcome measures. However, there was a chondroitinase-induced improvement in recovery from unskilled limb use deficits on the staircase forelimb reaching test toward sham-injured values at 28 days, which was not achieved by the vehicle-treated rats, indicating that there is some minor functional benefit of the increased sprouting induced by chondroitinase treatment. The current results, together with data from spinal cord injury models after chondroitinase intervention, suggest that a combinatorial approach with the addition of neurotrophins and rehabilitation would result in more robust axon sprouting and consequently improve behavioral outcome. [ABSTRACT FROM AUTHOR]

AbstractWe have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. 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 moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 μg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation. [ABSTRACT FROM AUTHOR]

AbstractThis study determined the effects of intraperitoneal sodium pyruvate (SP) treatment on the levels of circulating fuels and on cerebral microdialysis levels of glucose (MDglc), lactate (MDlac), and pyruvate (MDpyr), 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. MDpyrwas not altered after CCI-Sal, whereas MDlaclevels within the cerebral cortex significantly increased bilaterally (p< 0.05) and those for MDglcdecreased bilaterally (p< 0.05). MDpyrlevels 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 MDlacdecreased below CCI-Sal levels (p< 0.05) and the ipsilateral MDglclevels 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. [ABSTRACT FROM AUTHOR]

ABSTRACTHaving 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. [ABSTRACT FROM AUTHOR]

The present study determined the metabolic fate of [1, 2 13C2] glucose in male control rats and in rats with moderate lateral fluid percussion injured (FPI) at 3.5 h and 24 h post-surgery. After a 3-h infusion, the amount of 13C-labeled glucose increased bilaterally (26 in leftinjured cerebral cortex and 45 in right cerebral cortex) at 3.5 h after FPI and in injured cortex (45) at 24 h after injury, indicating an accumulation of unmetabolised glucose not seen in controls. No evidence of an increase in anaerobic glycolysis above control levels was found after FPI, as 13C-labeled lactate tended to decrease at both time points and was significantly reduced (33) in the injured cortex at 24 h post-FPI. A bilateral decrease in the 13C-labeling of both glutamate and glutamine was observed in the FPI rats at 3.5 h and the glutamine pool remained significantly decreased in the injured cortex at 24 h, suggesting reduced oxidative metabolism in both neuronal and astrocyte compartments after injury. The percentage of glucose metabolism through the pentose phosphate pathway (PPP) increased in the injured (13) and contralateral (11) cortex at 3.5 h post-FPI and in the injured cortex (9) at 24 h post-injury. Based upon the changes in metabolite pools, our results show an injury-induced decrease in glucose utilization and oxidation within the first 24 h after FPI. Increased metabolism through the PPP would result in increased NADPH synthesis, suggesting a need for reducing equivalents after FPI to help restore the intracellular redox state andor in response to free radical stress. [ABSTRACT FROM AUTHOR]