1. Five-carbon-atom organic acids (C-5 acids) have been administered intravenously to rabbits with ventriculocisternal perfusion and continuous electroencephalographic recording (EEG). The concentration of the acids in the cerebrospinal fluid (CSF) perfusate have been compared with changes in integrated low-frequency activity in the EEG.

2. The C-5 acids investigated were those accumulating in inborn errors of metabolism, i.e. isovaleric acid, β-methylcrotonic acid, tiglic acid and α-keto- and α-hydroxy-isovaleric acid. Their activity was compared with that of valeric acid.

3. Valeric acid and isovaleric acid produced coma and pronounced increase in slow-wave electrical activity and these changes paralleled the increase in concentration of the acids in the CSF perfusate.

4. The concentration of β-methylcrotonic acid and tiglic acid in the CSF perfusate reached values comparable with valeric acid and isovaleric acid but showed less encephalopathic activity. An interaction between β-methylcrotonic acid and isovaleric acid was observed.

5. Although the concentrations of α-ketoisovaleric acid and α-hydroxyisovaleric acid rose to the lesser extent in the CSF perfusate, changes in reusability of the animal and in the EEG recording were demonstrated.

6. It is concluded that all the C-5 acids tested have encephalopathic activity although this is lessened by the presence of either a double bond or an oxygenated functional group.

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