5-Aminolevulinate and 4, 5-dioxovalerate ions decrease GABAA receptor density in neuronal cells, synaptosomes and rat brain

Porphyrias are heme-associated metabolic disorders such as intermittent acute porphyria (IAP) and lead poisoning, where 5-aminolevulinate (ALA) accumulates. Effects of ALA on the CNS have been explained by ALA binding to GABAA receptors, followed by receptor lesions from oxyradicals and 4, 5-dioxovalerate (DOVA) generated from metal-catalyzed ALA oxidation by oxygen. We have characterized the effects of ALA and DOVA on GABAA receptor density in synaptosomes and neurons in vitro and also in brains of rats treated with ALA or succinylacetone methyl ester (SAME), a tyrosine catabolite derivative able to induce ALA accumulation. Radiolabeling assays revealed that following exposure to DOVA the concentration of synaptosomal GABAergic sites decreased by approximately 50%. Pretreatment with DOVA resulted in less GABAA receptor density in P19 and WERI cells and altered cell morphology. Furthermore, exposure to DOVA also induced a 5-fold increase in WERI cell mortality rate. Treatment with ALA resulted in loss of neuronal morphology and decrease of GABAA density in P19 neuronal cells. ALA and SAME treatment diminished the density of GABAergic receptors in the habenular complex and the parabigeminal nucleus of rat brain as studied by immunohistochemical procedures. Our results strongly suggest that ALA- and DOVA-promoted damage to GABAA receptors may contribute to the neurological manifestations of AIP and plumbism.