Summarywas lowered. However, the effect of DCA on the lactate level in the cerebrospinal fluid'in the patients has not been reported. The effects of dichloroacetate On the activity of the Therefore, we investigated the in vivo effects of small and large pyruvate deh~drogenase (PDH) and associated changes doses of DCA on the activity of the PDH complex in the brain in the lactate and glucose levels in rat brain were investigated in and consequent changes in the lactate and glucose levels in rats. vivo. The average activities of the active form of the PDH complex in the brain, liver and muscle of starved rats were respectively 0.40 f 0.04, 0.07 f 0.04, and 0.17 + 0.11 pmol/ min/g tissue, and amounted to 21, 11, and 16% of the total activity of the complex. Intraperitoneal injection of DCA (125 mg/kg) increased the percentage of the active form of the PDH complex in the brain, liver, and muscle to 107, 40, and 84%, respectively. DCA significantly lowered the lactate and glucose concentrations of the brain and blood. A lower dose of DCA (1 2.5 mg/kg) also caused significant increase in activity of the PDH complex in the brain, but did not significantly change the lactate or glucose concentration of the brain. These results suggest that DCA crosses the blood-brain barrier reasonably well. Abbreviations PDH, pyruvate dehydrogenase DCA, dichloroacetate Chronic congenital lactic acidosis of childhood is characterized by persistently high levels of blood pyruvate and lactate. Dietary control and other rational biochemical manipulations have been tried in attempts to lower the blood lactate level in patients with this disease, but with only limited success (2). In two patients with chronic lactic acidosis due to defects of pyruvate carboxylase (EC 6.4.1.1) and PDH (EC 1.2.4. I), the blood lactate and pyruvate were reduced to nearly normal levels by lipoic acid and dietary therapy, but despite this therapy the levels of lactate and pyruvate in the cerebrospinal fluid remained high, and neurologic deterioration continued ( I I, 16). Usually, the lactate and pyruvate levels in the cerebrospinal fluid are also elevated in patients with chronic congenital lactic acidosis. Therefore, it may be important to maintain the lactate level within a normal range not only in the blood but also in the cerebrospinal fluid in therapy of chronic congenital lactic acidosis.DCA is known to activate the PDH complex in various tissues in vitro by inhibiting PDH kinase (EC 2.7.1.99) (1,5,13). Moreover, administration of DCA to man and animals reduces the blood levels of lactate, pyruvate, and alanine by its action on PDH (6,15,17). Therefore, this drug has been used in attempts to treat chronic congenital lactic acidosis in humans (4,12,14). At the doses of DCA used, no neurologic improvement was observed during DCA therapy, although the blood lactate level
MATERIALS AND METHODS
Animals.Male Wistar rats weighing 1 70-195 g were given free access to water and laboratory chow.Chemicals. Sodium DCA was obtained from Tokyo Kasei Kogyo Co., (Tokyo,...
