Numerous studies using adult animal models suggest that dichloroacetate (DCA) may have neuroprotective properties by virtue of its ability to increase rates of metabolism and, therefore, clearance of brain
lactic acidosis, which may accumulate during
cerebral ischemia. We tested the hypothesis that postischemic DCA administration affects
lactate and
acid clearance to different extents in immature versus mature brain. 31P and 1H magnetic resonance spectroscopy were used to measure intracellular
acid and
lactate clearance rates in vivo in newborn and 1-month-old swine after a 14-min episode of transient near-complete global
ischemia. Simultaneous monitoring of extracellular
lactate efflux and clearance was measured in the same animals by in vivo microdialysis. Plasma
glucose concentrations were elevated in order to study animals with severe cerebral
lactic acidosis. Maximal levels of brain lactosis (16-20 micromol/g) and
acidosis (PHintracellular 5.8-6.0) were reached during the first 10 min of recovery and were the same in age groups and in subgroups either acting as controls or treated with DCA (200 mg/kg) given from the last minute of
ischemia to 5-7 min after
ischemia. For newborns, DCA administration improved the postischemic clearance rate of cerebral
acidosis and cerebral
phosphocreatine, with similar trends for the clearance of lactosis and increased rates of recovery of
nucleotide triphosphates, compared with controls. In contrast, DCA administration in 1-month-olds resulted in a modest trend for improvement of cerebral
lactate clearance, but did not affect
acid clearance or the recovery rate of
phosphocreatine or
nucleotide triphosphates. Extracellular brain
lactate concentrations had similar relative increases and rates of decline for subgroups of either age treated with DCA versus controls. The results of this study indicate that postischemic DCA administration helps to resolve cerebral
acidosis to a greater degree in immature than more mature brain, suggesting that DCA may have cerebroprotective properties for neonatal
hypoxic-ischemic encephalopathy.