Cytoplasmic calcium mediates oxidative damage in an excitotoxic /energetic deficit synergic model in rats.
Excessive calcium is responsible for triggering different potentially fatal metabolic pathways during neurodegeneration. In this study, we evaluated the role of calcium on the oxidative damage produced in an in vitro combined model of excitotoxicity/energy deficit produced by the co-administration of quinolinate and 3-nitropropionate to brain synaptosomal membranes. Synaptosomal fractions were incubated in the presence of subtoxic concentrations of these agents (21 and 166 microm, respectively). In order further to characterize possible toxic mechanisms involved in oxidative damage in this experimental paradigm, agents with different properties - dizocilpine, acetyl L-carnitine, iron porphyrinate and S-allylcysteine - were tested at increasing concentrations (10-1000 microm). Lipid peroxidation was assessed by the formation of thiobarbituric acid-reactive substances. For confirmatory purposes, additional fractions were incubated in parallel in the presence of the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Under physiological conditions of extracellular calcium availability, synaptomes exposed to both toxins displayed an increased lipoperoxidation (76% above controls), and this effect was partially attenuated by the tested agents as follows: dizocilpine = iron porphyrinate > acetyl L-carnitine > S-allylcysteine. When the incubation medium was deprived of calcium, the lipoperoxidative effect achieved in this experimental paradigm was still high (49% above the control), and the order of attenuation was: iron porphyrinate > S-allylcysteine > acetyl L-carnitine > dizocilpine. BAPTA-AM was effective in preventing the pro-oxidant action of both toxins, promoting even lower peroxidative levels than those quantified under basal conditions. Our results suggest that the lipid peroxidation induced in synaptosomal fractions by quinolinate plus 3-nitropropionate is largely dependent on the cytoplasmic concentrations of calcium.
Pérez-De La Cruz
Verónica
V
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México DF 14269, México.
Konigsberg
Mina
M
Pedraza-Chaverri
José
J
Herrera-Mundo
Nieves
N
Díaz-Muñoz
Mauricio
M
Morán
Julio
J
Fortoul-van der Goes
Teresa
T
Rondán-Zárate
Adrián
A
Maldonado
Perla D
PD
Ali
Syed F
SF
Santamaría
Abel
A
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009574:Nitro Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011422:Propionates / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure
D009574:Nitro Compounds; D011422:Propionates; D017378:Quinolinic Acid; C015392:3-nitropropionic acid; D002118:Calcium