Abstract
ACUTE attacks of the hereditary hepatic porphyrias are frequently accompanied by neuropsychiatrie symptoms. The presentation of nervous system involvement varies; in decreasing order of frequency, there may be motor neuropathy, confusion, psychiatric manifestations, hyperexcitability and epileptic-type seizures1. Psychiatric manifestations include depression, anxiety, insomnia and an organic brain syndrome2. Although the aetiology of the neural dysfunction in the acute attack is unknown, several mechanisms have been suggested at a neurochemical level. It is possible that porphyrin precursors, which are produced in excess by the liver during acute episodes, gain access to the nervous system and exert direct neurotoxic effects3–5; alternatively, a metabolic defect in haem biosynthesis in nerve cells might result in a functional haemoprotein deficiency which becomes critical at the time of the acute attack6. The porphyrin precursor, δ-aminolaevulinic acid (δ-ALA), exhibits various effects in mammalian central nervous tissue preparations. It inhibits high-affinity uptake and increases efflux of γ-aminobutyric acid (GABA)3 and L-glutamate4 in rat cortical synaptosomes; it also inhibits the (Na+ + K+) ATPase isolated from rabbit brain and red blood cells7. These effects occur only at relatively high concentrations of δ-ALA (at least 10−4M), and it is very unlikely that such concentrations are reached in the brain during acute porphyric attacks8. Recently, there has been strong evidence that release of GABA is subject to negative feedback control through presynaptic receptors on GABAergic terminals9–11. Here we report that δ-ALA inhibits potassium-stimulated release of GABA from preloaded synaptosomes, probably by acting as an agonist at these presynaptic receptors. This effect is evident at concentrations of δ-ALA (10−6M) which are well within levels recorded in the cerebrospinal fluid of porphyric patients showing neuropsychiatrie symptomatology12.
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References
Eales, L. S. Afr. J. Lab. clin. Med. 9, 151–162 (1963).
Tschudy, D. P. in Duncan's Diseases of Metabolism (eds Bondy, P. K. & Rosenberg, L. E.) 775–824 (Saunders, Philadelphia, 1974).
Brennan, M. J. W. & Cantrill, R. C. J. Neurochem. 32, 1781–1786 (1979).
Brennan, M. J. W. & Cantrill, R. C. J. Neurochem. (in the press).
Kramer, S., Becker, D. & Viljoen, D. S. Afr. med. J. 47, 1735–1738 (1973).
Meyer, U. A. & Schmid, R. in Brain Dysfunction in Metabolic Disorders (ed. Plum, F.); Res. Publs Ass. Res. nerv. ment. Dis. 53, 211–223 (1974).
Becker, D. M., Viljoen, J. D. & Kramer, S. Biochim. biophys. Acta 225, 26–34 (1971).
Shanley, B. C., Neethling, A. C., Percy, V. A. & Carstens, M. S. Afr. med. J. 49, 576–580 (1975).
Snodgrass, S. R. Nature 274, 392–394 (1978).
Mitchell, P. R. & Martin, I. L. Nature 274, 904–905 (1978).
Brennan, M. J. W., Cantrill, R. C. & Epstein, H. 4th natn. Congr. S. Afr. biochem. Soc., 102 (1979).
Sweeney, V. P., Pathak, A. M. & Asbury, A. K. Brain 93, 369–380 (1970).
Brennan, M. J. W. & Cantrill, R. C. J. Neurochem. 31, 1339–1341 (1978).
Cantrill, R. C. & Brennan, M. J. W. Experientia (in the press).
McGillion, F. B., Thompson, G. G., Moore, M. R. & Goldberg, A. Biochem. Pharmac. 23, 472–474 (1974).
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BRENNAN, M., CANTRILL, R. δ-Aminolaevulinic acid is a potent agonist for GABA autoreceptors. Nature 280, 514–515 (1979). https://doi.org/10.1038/280514a0
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DOI: https://doi.org/10.1038/280514a0
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