Use of fluorocitrate and fluoroacetate in the study of brain metabolism.
Fluoroacetate and its toxic metabolite fluorocitrate cause inhibition of aconitase. In brain tissue, both substances are preferentially taken up by glial cells and leads to inhibition of the glial TCA cycle. It is important to realise, however, that the glia-specificity of these compounds depends both on the dosage and on the model used. The glia-inhibitory effect of fluorocitrate as obtained by intracerebral microinjection in vivo is reversible within 24 h. A substantial inhibition of the glial TCA cycle by systemic administration of fluoroacetate requires a lethal dose. Inhibition of the glial aconitase leads to accumulation of citrate and to a reduction in the formation of glutamine. Whereas the former is likely to be responsible for the main toxic effect of these compounds possibly by chelation of free calcium ions, it is the latter that has received most attention in the study of glial-neuronal interactions, since glutamine is an important precursor for transmitter glutamate and GABA.
Fonnum
F
F
Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller.
Johnsen
A
A
Hassel
B
B
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D002250:Carbon Radioisotopes; D002951:Citrates / Q000493:pharmacokinetics* / Q000633:toxicity; D002952:Citric Acid Cycle; D005463:Fluoroacetates / Q000493:pharmacokinetics* / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002250:Carbon Radioisotopes; D002951:Citrates; D005463:Fluoroacetates; D005973:Glutamine; D001224:Aspartic Acid; C007744:fluorocitrate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid