VALPROATE INDUCED ENCEPHALOPATHY MAY BE RELATED TO INHIBITION IN a-KETOGLUTARATE DEHYDROGENASE ACTIVITY IN THE BRAIN
Abstract number :
2.295
Submission category :
Year :
2003
Submission ID :
3802
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Nga H.T. Nguyen, Evy G. Iversen, Leif Gjerstad, Erik Tauboll, Bjornar Hassel Division of Environmental Toxicology, Norwegian Defence Research Establishment, Kjeller, Norway; Department of Neurology, Rikshospitalet, University of Oslo, Oslo, Norway
Valproate may induce encephalopathy with cognitive impairment. Inhibition of alpha-ketoglutarate dehydrogenase (a-KGD), which is a rate-limiting step in neuronal energy metabolism, is associated with cerebral dysfunction including dementia. The aim of the study was to investigate whether VPA might induce a change in a-KGD activity as a possible mechanism for VPA induced encephalopathy.
Twenty-three male Wistar rats were fed with VPA 0, 200 or 400 mg/kg twice daily for 90 days, giving therapeutically relevant serum concentrations. Approximately 4 h after last dose the animals were killed and brain tissue from frontal cortex and hippocampus was collected and frozen together with serum samples. Relevant enzyme activities and tissue levels of amino acids were determined.
In the frontal cortex, VPA caused a 20% decrease in a-KGD activity together with a reduction in glutamate and GABA levels, and a reduction in GAD/GABA-T activity ratio. The activity of NAD-dependent glycerol-3-phosphate dehydrogenase increased significantly in the frontal cortex, possibly reflecting energy generation through an alternative pathway. In the hippocampus, a-KGD activity and glutamate and GABA levels were unchanged. However, the GAD/GABA-T activity ratio decreased. The hippocampal level of taurine increased by ~10%.
Chronic VPA treatment decreases a-KGD activity in the frontal cortex. This implies reduced energy metabolism in this part of the brain and may contribute to the cognitive symptoms sometimes seen with VPA therapy.