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Chronic valproate administration produces hepatic dysfunction and may delay brain maturation in infant mice

Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, and the Division of Neurology, St. Louis Children's Hospital, St. Louis, MO.

Infant mice (2 to 4 days old) received valproate (100 or 200 mg per kilogram body weight) subcutaneously once daily for 5 days. Both dosages decreased plasma ß-hydroxybutyrate levels to about one-third of the control value, in the face of normal free fatty acid and glycerol levels. At 200 mg per kilogram of valproate, there were significant decreases in brain weight and brain K + content. Both doses produced metabolite changes in brain compatible with a reduced metabolic flux through the glycolytic pathway and the citric acid cycle. Valproate reduced brain aspartate but did not increase brain GABA levels in infant mice. At 200 mg per kilogram of valproate, brain glutamate decreased and taurine levels increased. Two hundred milligrams per kilogram of valproate caused a profound reduction of liver glycogen stores.

The apparent decrease in cerebral metabolic rate, reduced glutamate and aspartate, and increased levels of taurine in brain may relate to the anticonvulsant action of valproate. Together with the decreased brain weight and K- content, the findings are also compatible with maturational delay. Decreased ketonemia and liver glycogen content may relate to the hepatic toxicity associated with valproate administration in infants and children.

Address correspondence and reprint requests to Dr. Thurston. Department of Pediatrics, St Louis Children's Hospital, 500 S. Kingshighway Boulevard, P. 0. Box 14871, St. Louis, MO 6318.

Presented in part at the eleventh annual meeting of the American Society for Neurochemistry, Houston, TX, March 2–7, 1980, and at the ninth national meeting of the Child Neurology Society, Savannah, GA, October 2–4, 1980.

Supported by USPHS research grants Nos. NS 06163 and NS 15660, the Washington University Resource for Biomedical Mass Spectrometry Grant No. USPHS RR 00954 and the Allen P. and Josephine B. Green Foundation, Mexico, Missouri. W. Edwin Dodson and James E. Carroll are Academic Career Development awardees of the NINCDS (Nos. 1-KO7-NS 11074 and 5-KO7-NS 00386, respectively!.

Accepted for publication January 19, 1981.

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