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.

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.

In order to assess the role of circulating blood in early microglial activation after traumatic brain injury (TBI), controlled cortical impact injury was applied to adult rat brain slices (400 microm in thickness) and the microglial response was examined. The complement receptor (CR3) expression and morphological transformation of the microglia were evaluated by OX42 immunohistochemistry. At 5 min following injury, activated microglia with intense CR3 expression appeared throughout the hemisphere on the injured side. In contrast, the morphology and CR3 expression of the microglia on the contralateral side were indistinguishable from those of the resident ramified microglia seen in normal brains. At 30 min following injury, microglial activation was more pronounced on the injured side, while the microglia on the contralateral side still retained a ramified morphology. These results are consistent with our previous observations made in in vivo experiments, which indicate that, as the brain slice paradigm excludes variables arising from the circulating blood, the rapid and widespread microglial activation observed following TBI can not be attributed exclusively to the infiltration of blood-borne macrophages or molecules. Rather this activation is most likely caused by intrinsic mechanisms within the brain tissue, such as traumatic depolarization.