Cytoplasmic calcium mediates oxidative damage in an excitotoxic /energetic deficit synergic model in rats

Abstract

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.

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

“…The main reasons these variations occur is due to the elevated metabolic rate of neuronal cells, and the lower capacity for energy substrate storage. Consequently, the deficiency in energy substrate supplies produces important changes in the intracellular and extracellular ionic concentrations, and, as a result, changes in membrane potential [38]. In contrast, little is known about the effect of QA on brain energy metabolism.…”

“…Whether this metabolic disturbance is a risk factor for several obesity-associated disorders including diabetes, neuronal dysfunction, or metabolic syndrome remains to be determined [37]. In addition, QA has been reported to be involved in the pathogenesis of different neurological disorders such as Alzheimer's disease, dementia, hepatic encephalopathy and Huntington's disease itself [38]. Similarly, QA can mimic some symptoms of early stage HD, including the loss of projection of GABAergic neurons with a relative preservation of interneurons, and allows for the study of therapeutics, such as transplantation [39].…”

“…Free radicals have also been demonstrated to be responsible for progressive mitochondrial alteration, resulting in the inhibition of complexes II, III, and II-III in the electron transport chain, with a consequent reduction of ATP levels, which in turn may contribute to neurodegeneration. Oxidative stress has been demonstrated as part of its mechanism of toxicity [38]. Mitochondrial disturbances result in an energy deficit and the production of free radicals, which results in disruption of membrane potential and in oxidative stress.…”

Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

“…Therefore, the delayed and persistent increase in the antioxidant capacity after QUIN insult may be a cellular adaptive response, probably contributing to the decrease in ROS levels [52]. Additionally, it was observed in synaptosomal fractions exposed to QUIN and 3-nitropropionic acid at nontoxic concentration, a synergic effect in oxidative markers which was just partially prevented by MK-801 [79]. …”

Effect of PD98059, a Selective MAPK3/MAPK1 Inhibitor, on Acute Lung Injury in Mice

“…In addition, the elevation of intracellular Ca 2 + concentration causes release of proteases (e.g., leukocyte elastase or cathepsin G) and formation of reactive oxygen species (ROS) (6), both ofwhich not only destroy invading particles but also damage cells and tissues of the host. Moreover, ROS generation induced by intracellular Ca 2 + elevation causes lipid peroxidation and DNA single strand damage (7). Interference with the generation or action of these pro-inflammatory mediators exerts beneficial effects in a variety of inflammation models including the carrageenan-induced paw edema and pleurisy model (8).…”