Bilirubin-induced changes in brain energy metabolism after osmotic opening of the blood-brain barrier

Acute and residual effects of blood-brain barrier disruption and bilirubin on brain metabolism were studied in a rat model after osmotic opening of the blood-brain barrier under pentobarbital anesthesia. Arabinose (1.5 M) was infused via the right external carotid artery over 30 s, resulting in opening of the barrier within the right hemisphere. Two min later, bilirubin was infused i.v. over 3 min, raising the serum bilirubin concentration to 37-44 mg/dL (633-752 mumol/L). The animals were euthanized at 15 min or 4 h by freezing the brain in situ. Opening the blood-brain barrier produced small changes in cerebral energy metabolism in some animals at 15 min. Compared with saline-infused control animals, two out of nine rats had decreased brain phosphocreatine and three out of nine developed increased brain lactate levels. Infusion of bilirubin in rats with a disrupted blood-brain barrier produced profound decreases in brain energy metabolites, glucose, and glycogen and a markedly increased lactate/pyruvate ratio at 15 min. The markedly increased lactate in the presence of normal or low pyruvate in bilirubin-treated animals indicates accumulation of NADH and probably reflects severe mitochondrial dysfunction. Four h after the arabinose/bilirubin infusions, the barrier would be expected to be repaired and bilirubin levels were negligible, but two out of five arabinose and three out of six bilirubin rats continued to have severely altered brain metabolism indicating residual brain injury in some animals.