Effects of 5-aminolevulinic acid on the glutamatergic neurotransmission.
The haem precursor 5-aminolevulinic acid (ALA) has been proposed to be involved in the neurological dysfunctions presented by patients with acute porphyrias. The effects of ALA on the [3H]glutamate and [3H]MK-801 (dizocilpine) binding to rat cortical membranes and on [3H]glutamate uptake by rat astrocyte cultures were evaluated in the present study in order to elucidate the interaction of ALA with the glutamatergic system and its possible contribution to the in vivo excitatory properties of ALA. ALA (0-1mM) did not affect the binding of 100 nM [3H]glutamate, nor the equilibrium binding constants (K(d) and B(max)) of this neurotransmitter in rat or human cortical membranes. The binding of the NMDA-channel blocker, [3H]MK-801, was not affected by ALA (0-10mM) either. ALA (0-3mM) dose-dependently inhibited glutamate uptake by astrocyte cultures. ALA significantly reduced both the K(m) and V(max) of glutamate uptake indicating an uncompetitive inhibition. The inhibitory effect was irreversible and apparently related to the selective inhibition of the GLT-1 (EAAT2) subtype of glutamate transporter. The finding that ALA significantly increased astrocyte lipoperoxidation in astrocytes incubated under these conditions suggests that the inhibitory effect of ALA might be related to an oxidative damage of the transporter. We propose that the inhibition of glutamate uptake may underlie ALA-induced convulsions.
Emanuelli
Tatiana
T
Departamento de Ciência e Tecnologia de Alimentos, Centro de Ciências Rurais, Universidade Federal de Santa Maria, Campus-Camobi, 97105-900, Santa Maria, RS, Brazil. tati@ccr.ufsm.br
Pagel
Fernanda W
FW
Porciúncula
Lisiane O
LO
Souza
Diogo O
DO
D000622:Aminolevulinic Acid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D009419:Nerve Tissue Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D017392:Thiobarbituric Acid Reactive Substances; D018698:Glutamic Acid; D003994:Bucladesine; D016291:Dizocilpine Maleate; D000622:Aminolevulinic Acid; C022616:thiazolyl blue