The prooxidant effect of 5-aminolevulinic acid in the brain tissue of rats: implications in neuropsychiatric manifestations in porphyrias.
5-Aminolevulinic acid (ALA), a heme precursor accumulated during the clinical expression of acute intermittent porphyria, lead poisoning, and tyrosinosis, has been hypothesized to act as an endogenous source of oxyradicals. We now report oxidative effects on brain tissue of rats submitted to ALA treatment. Upon acute treatment (40 mg/kg body weight) increased total nonheme iron in the cortex (20%) was observed. After prolonged ALA administration (40 mg/kg body weight on alternate days during 2 weeks), the following indicators of oxidative stress were found to be significantly increased: CuZnSOD activity (67%) in total brain homogenate, total iron (68%) and ferritin (71%) in the cortex, ferritin in striatum (44%), protein carbonyls in homogenate of cerebral cortex (threefold) and 45Ca2+ uptake by cortical synaptosomes (45%). In addition, synaptic membranes prepared from whole brain assayed with the radioligand 3H-muscimol, revealed increased Kd values (twofold) of the high-affinity GABAergic receptor binding and formation of protein carbonyl groups, thiobarbituric acid reactive products, and conjugated dienes. In vitro, ALA produced similar effects upon the high affinity 3H-muscimol binding. No apparent alteration of either dopaminergic or serotonergic [3H]-ligand binding was observed. These results argue in favor of ALA-triggered oxidative stress in brain accompanied by iron metabolism alterations and GABAergic receptor damage, which may be implicated in the neuropsychiatric manifestations of the aforementioned porphyrias.
Demasi
M
M
Instituto de Química Universidade de São Paulo, Brazil.
Penatti
C A
CA
DeLucia
R
R
Bechara
E J
EJ
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D011164:Porphyrias / Q000503:physiopathology* / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013570:Synaptic Membranes / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D009419:Nerve Tissue Proteins; D016877:Oxidants; D011956:Receptors, Cell Surface; D013438:Sulfhydryl Compounds; D006418:Heme; D000622:Aminolevulinic Acid; D005293:Ferritins; D002374:Catalase; D005979:Glutathione Peroxidase; D002118:Calcium