Induced mitochondrial failure in the feline brain: implications for understanding acute post-traumatic metabolic events

Objective: Recently, evidence has become available implicating mitochondria l failure as a crucial factor in the pathogenesis of acute brain damage fol lowing severe traumatic brain injury (TBI). However, it remains unclear how mitochondrial dysfunction affects cerebral metabolism. Therefore the aim o f the study was to evaluate the impact of `isolated' mitochondrial failure on local cerebral metabolism. Methods: Cerebral mitochondrial metabolism wa s blocked by local microdialysis perfusion with cyanide in seven cats. Loca l brain tissue oxygen tension (p(tiO2)), carbon dioxide tension (p(tiCO2)) and pH, as well as extracellular cerebral fluid, glucose, lactate, pyruvate and glutamate were monitored, using a Neurotrend sensor-and microdialysis, respectively. Tissue oxygen consumption was measured in a microrespirometr ic system, and ultrastructural changes evaluated via electron microscopy. R esults: Brain tissue oxygen tension increased from a baseline of 31 +/-9 mm Hg to 84 +/- 30 mmHg after 60 min of cyanide perfusion (P <0.05), concomita nt a decrease in oxygen consumption from 14.45 +/-3.91 mul/h/mg to 10.83 +/ -1.74 mul/h/mg (P <0.05). Brain tissue pH was decreased after 60 min of cya nide perfusion (6.83 +/-0.16) compared to baseline (7.07 +/-0.39) (P <0.05) , whereas p(tiCO2), did not show significant changes. Lactate massively inc reased from a baseline of 599 +/- 270 mu mol/l to 2609 +/- 1188 mu mol/l im mediately after cyanide perfusion (P <0.05). The lactate:glucose ratio incr eased from 0.79 +/-0.15 before cyanide perfusion to 6.40 +/-1.44 at 40 min after cyanide perfusion (P <0.05), while no significant changes in the lact ate:pyruvate ratio could be observed. Glutamate increased from a baseline o f 11.6 +/-7.2 mu mol/l to 61.4 +/- 44.7 mu mol/l after cyanide perfusion (P <0.05). Conclusion: The results of this study show that `isolated' cerebra l mitochondrial failure initiates changes in cerebral substrates and bioche mistry, which are very similar to most of the changes seen after severe hum an head injury, except for the early fall in p(tiO2), further indicating a crucial involvement of mitochondrial impairment in the development of brain damage after TBI. (C) 2001 Elsevier Science B.V. All rights reserved.