In vivo protection by melatonin against delta-aminolevulinic acid-induced oxidative damage and its antioxidant effect on the activity of haem enzymes.

Accumulation of delta-aminolevulinic acid (ALA), as it occurs in acute intermittent porphyria, is a potential endogenous source of reactive oxygen species (ROS) which can then produce oxidative damage to cell structures and macromolecules. This in vivo study investigated whether melatonin could prevent the deleterious effects of ALA. Rats were injected i.p. for 2 weeks with ALA (40 mg/kg on alternate days) and/or with melatonin (50 microg/kg or 500 microg/kg daily). Administration of pharmacological doses of melatonin reduced and/or prevented ALA-induced lipid peroxidation (LPO) in both cerebral cortex and cerebellum, providing further evidence of melatonin's action as a ROS scavenger. Administration of pharmacological concentrations of melatonin to ALA-injected rats showed the protective properties of melatonin on the activities of both porphobilinogen-deaminase and delta-aminolevulinate dehydratase (ALA-D) in the cerebral cortex; the effect on ALA-D activity was unexpectedly high (at least 6-fold), indicating that, besides acting as a scavenger of hydroxyl radicals, melatonin may exert its protection on ALA-D through other mechanisms, such as increasing mRNA levels of antioxidant enzymes or/and inducing glutathione peroxidase activity. The possibility that changes in the expression of antioxidant enzymes could affect the expression of other proteins, even those not related to the cellular ROS homeostasis, should also not be discarded. The potential use of melatonin as an antioxidant and for its reactivating properties in the treatment of acute porphyrias is considered.

Melatonin's antioxidant protection against delta-aminolevulinic acid-induced oxidative damage in rat cerebellum.

delta-aminolevulinic acid (ALA) promotes the generation of reactive oxygen species (ROS). Accumulation of ALA, as occurs in acute intermittent porphyria (AIP), is a potential endogenous source of ROS, which can then exert oxidative damage to cell structures. In this work we investigated the role of pharmacological concentrations of melatonin on the deleterious effect of ALA and its effect on porphyrin biosynthesis. Rat cerebellum incubations were carried out with either ALA (1.0 mM) together with increasing concentrations of melatonin (0.1-2.0 mM) or 2.0 mM melatonin together with varying ALA concentrations (0.05-2.0 mM) for different times (1-4 hr). ALA-induced lipid peroxidation was significantly diminished by melatonin in a concentration-dependent manner. In all conditions 2.0 mM melatonin restored malondialdehyde levels to control values. In incubations without ALA, melatonin markedly reduced (36-40%) the basal levels of lipid peroxidation when compared with the corresponding controls. ALA uptake and porphyrin accumulation were increased 30% in incubations with 1.0-2.0 mM ALA for 4 hr in the presence of 2.0 mM melatonin, providing evidence for the involvement of ALA-promoted ROS in the damage of enzymes related to porphyrin biosynthesis. These results are further support for the protective role of melatonin against oxidative damage induced by ALA; this protective action of melatonin is probably due to melatonin's antioxidant and free radical scavenger properties. The development of a new therapeutic approach for AIP patients employing melatonin alone or in combination with conventional treatments should be considered.