Neurochemical aspects of porphyria. Studies on the possible neurotoxicity of delta aminolaevulinic acid
Shanley, B. C.
Neethling, A. C.
Percy, V. A.
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It has been proposed that delta aminolaevulinic acid (ALA), which is overproduced in the inherited hepatic porphyrias, may be responsible for the neurological manifestations of the acute attacks seen in these disorders. Studies were conducted in rats to test the neurotoxicity of ALA. It was found that, after intraperitoneal or subcutaneous injections, ALA is rapidly eliminated via the kidneys. In nephrectomised animals sustained elevation of blood ALA concentration was demonstrated, but despite this, brain uptake was extremely low. Experiments on incorporation of [4 14C] ALA into brain haem yielded similar information. After intraventricular injection of [4 14C] ALA, significant uptake by brain tissue occurred. The subsequent disappearance of ALA was moderately rapid and was virtually complete within 24 hours. Uptake of [4 14C] ALA was apparently significantly greater in the hypothalamus than in other brain areas. The subcellular distribution of radioactivity did not reveal any preferential uptake by nerve endings. Intraventricular injection of unlabelled ALA revealed definite but transitory neurotoxic effects in doses of 3 micromoles and greater. These include involuntary movements and ataxia. No effect of ALA administration on brain protein synthesis could be demonstrated. It is concluded that ALA does have effects on the nervous system in vivo, but the significance of these effects in relation to the pathogenesis of the neurological manifestations of acute porphyria is questionable.