Basic science and clinical research has shown that traumatic brain injury (TBI) results in acute increases in glucose uptake (hyperglycolysis) to re-equilibrate ionic and neurochemical imbalances and, while secondary events placing energy demands on injured tissue may recur thereafter, the resting cerebral metabolic rates of glucose (CMRglc) and oxygen are decreased for prolonged periods after TBI. Many questions remain unanswered about the causes and consequences of these altered metabolic states, whether interventions can be made to improve the metabolic response to injury, and the consequences of these interventions. Using our model of unilateral controlled cortical impact (CCI) injury, which produces profound energy crisis followed by widespread depression of CMRglc, focal and remote neuronal injury, alterations in glycolytic enzymes and co-factors, free radical-induced oxidative and nitrosative stress, altered flux of glucose carbons through glycolysis, oxidative and intermediary metabolic pathways, and enduring functional deficits, we propose to address key questions related to metabolic dysfunctions after TBI. i) Can we improve CMRglc, reduce neuronal damage, or improve neurological outcomes by administering exogenous glucose or a downstream, alternative fuel such as pyruvate? ii) When, and for how long, should these exogenous fuels be administered? iii) What are the effects of exogenous glucose or pyruvate on the cytosolic redox state and glycolytic enzyme activity? iv) Do exogenous fuels improve bioenergetics and/or induce changes in glucose metabolic pathways? v) Does administration of exogenous fuels come at the expense of increased oxidative/nitrosative stress, and does this depend on the fuel delivered? We will assess effects of glucose or pyruvate administration on the magnitude and regional extent of decreased CMRglc using standard 14C- 2DG autoradiography and assess extent of neuronal damage in these same animals. Markers of oxidative/nitrosative stress will be evaluated using immunocytochemistry and Western blots. Biochemical assays will be used to assess exogenous fuel effects on cytosolic NAD+ levels and activity of the key glycolytic enzyme, GAPDH. Sensorimotor and cognitive functions will be assessed over weeks after glucose or pyruvate administration and histopathology evaluated 1 month post-CCI. NMR spectroscopy will be used to evaluate effects of glucose and pyruvate on bioenergetics and metabolic fate of 13C-labeled glucose.
This work will provide insights regarding the therapeutic utility of providing glucose or pyruvate after traumatic brain injury and the mechanisms by which these metabolic substrates may improve cell viability, cerebral metabolism and brain bioenergetics. The project has direct relevance to the current clinical practice of tightly controlling blood glucose and questions of proper metabolic support for head injury patients.
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