Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sodium valproate (VPA) is used in the acute treatment of status epilepticus and mania. We studied the acute effect of VPA on cerebral energy metabolism in awake mice that received VPA 400 mg kg(-1) and [1-(13)C]glucose or [2-(13)C]acetate. At 25 min, (13)C NMR spectroscopy of brain extracts indicated inhibition of the tricarboxylic acid (TCA) cycle, as could be seen from the accumulation of [4-(13)C]glutamate and reduction in [(13)C]aspartate formation. Concomitantly, the level of ATP was reduced by 40%. To identify the enzymatic step at which the TCA cycle was inhibited [U-(14)C]alpha-ketoglutarate was injected intracerebrally. Inhibition of alpha-ketoglutarate dehydrogenase was evident at 25 min, as shown by accumulation of [(14)C]glutamate. At 45 min the inhibition of alpha-ketoglutarate dehydrogenase was reversed, shown by both (13)C- and (14)C-labeling, and the ATP level was normalized. The study shows for the first time that acute administration of VPA causes inhibition of the TCA cycle activity in vivo. The reduction in brain ATP would be expected to reduce neuronal excitability through modulation of sodium channels which may be clinically advantageous in the initial phase of VPA treatment.
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PMID:The acute effect of valproate on cerebral energy metabolism in mice. 1173 32

Status epilepticus (SE) in humans and animal models results in significant cerebral damage and an increased risk of subsequent seizures, associated with a characteristic pattern of neuronal loss particularly affecting the hippocampus. Seizure related cell death is considered to be excitotoxic, but studies have been limited, concentrating on terminal events rather than initial mechanisms. We have studied the biochemical events in the first few days following SE. Self-sustaining limbic SE was induced in adult rats using perforant path stimulation, and animals were allowed to recover. Biochemical studies were performed at 16, 44 h and 8 days following SE, using spectrophotometric enzyme assays and HPLC on regional brain homogenates compared with those from sham-operated controls. Haematoxylin and eosin histology was also undertaken at each time point. Brain aconitase and alpha-ketoglutarate dehydrogenase (alphaKDH) activity were both significantly (P<0.05) reduced by approximately 20% in the first 16-44 h following status, but had returned to normal by 8 days. These enzymes are part of the tri-carboxylic acid (Krebbs) cycle in the mitochondrial matrix, and are known to be sensitive to free radical, especially peroxynitrite damage. There was a similar decrease in reduced glutathione levels. Histological studies confirmed evidence of acute neuronal damage up to 44 h, and neuronal loss by 8 days. This is the first in vivo demonstration of this pattern of mitochondrial dysfunction and loss of brain glutathione following SE. The pattern of abnormalities is consistent with reversible mechanisms being involved in excitotoxic cell damage. This, together with the timing of changes, suggests new avenues for therapeutic intervention.
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PMID:Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat. 1190 34