Metabolic, neurochemical, and histological responses to activation following traumatic brain injury in the rat

Metabolic depression is a chronic component of the pathophysiology of traumatic brain injury (TBI). Previous studies have demonstrated that the cortical metabolic response to peripheral somatosensory activation is impaired during the period of metabolic depression following TBI; however, without electrophysiological measurement of cell firing in the cortex, circuit dysfunction cannot be excluded as the primary cause of impaired responsiveness.; In these studies, adult rats were subjected to vibrissa motor cortex stimulation following mild-moderate lateral fluid percussion injury (LFPI). 2-Deoxyglucose autoradiography studies revealed that at all timepoints following injury, stimulation induced a robust metabolic response; however, the relative increase in metabolic response was greatest at 1 day following LFPI due to the underlying metabolic depression. Microdialysis studies confirmed that the increased metabolic response was accompanied by an exacerbated increase in extracellular lactate and decrease in extracellular glucose in response to stimulation at I day following LFPI. Finally, cresyl violet histology demonstrated that this stimulation-induced increase in anaerobic glycolysis resulted in an increase in stimulation-induced lesion volume, suggesting that direct cortical stimulation results in a secondary injury in the TBI brain.; The efficacy of cyclosporin A (CsA), a selective inhibitor of the mitochondrial permeability transition, in ameliorating the anaerobic glycolysis response to stimulation following injury was studied. CsA exacerbated both the neurochemical and histological responses to stimulation following injury compared to FK506 controls. Co-administration of CsA and PBN, a free radical scavenger, restored the histological response to control levels, suggesting that increased free radical production associated with improved mitochondrial function is the mechanism for CsA-induced exacerbation of stimulation-induced damage.; In summary, direct cortical stimulation following TBI does result in a metabolic response reflecting anaerobic glycolysis. Attempting to ameliorate this response with CsA is ineffective due to secondary effects of mitochondrial protection. These studies provide important insight for the timing of rehabilitation and physical therapy and for the investigation of potential therapeutics for the treatment of human head injury.