Clínica

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    Alcohol hangover: impairments in behavior and bioenergetics in central nervous system
    (Biocell, 2016-4-16) Karadayian, Analía G. ; Bustamante, Juanita ; Lores-Arnaiz, Silvia
    Alcohol hangover (AH) is defined as the temporary state after alcohol binge-like drinking, starting when EtOH is absent in plasma. Results from our laboratory have shown behavioral impairments and mitochondrial dysfunction in an experimental model of AH in mice. Our model consisted in a single i.p. injection of EtOH (3.8 g/kg BW) or saline solution in male and female mice, sacrificing the animals 6 hours after injection. Motor and affective behavior together with mitochondrial function and free radical production were evaluated in brain cortex and cerebellum during AH. Results showed that hangover animals exhibited a significant reduction in neuromuscular coordination, motor strength and locomotion together with a loss of gait stability and walking deficiencies. Moreover, an increment in anxiety-like behavior together with fear-related phenotype and depression signs were observed. In relation to bioenergetics metabolism, AH induced a reduction in oxygen uptake, inhibition of respiratory complexes, changes in mitochondrial membrane permeability, decrease in transmembrane potential, increase in O2•- and H2O2 production and impairment in nitric oxide metabolism. All together our data suggest that the physiopathological state of AH involves behavioral impairments and mitochondrial dysfunction in mouse brain cortex and cerebellum showing the long lasting effects of acute EtOH exposure in CNS.
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    Brain cortex mitochondrial bioenergetics in synaptosomes and non-synaptic mitochondria during aging
    (Neurochemical research, 2016-1-28) Lores-Arnaiz, Silvia ; Lombardi, Paulina ; Karadayian, Analía G. ; Orgambide, Federico ; Cicerchia, Daniela ; Bustamante, Juanita
    Alterations in mitochondrial bioenergetics have been associated with brain aging. In order to evaluate the susceptibility of brain cortex synaptosomes and non-synaptic mitochondria to aging-dependent dysfunction, male Swiss mice of 3 or 17 months old were used. Mitochondrial function was evaluated by oxygen consumption, mitochondrial membrane potential and respiratory complexes activity, together with UCP-2 protein expression. Basal respiration and respiration driving proton leak were decresed by 26 and 33% in sunaptosomes from 17-months old mice, but spare respiratory rate was decreased by 45% in brain cortex non-synaptic mitochondria from 17-month-old mice, as compared with young animales, but respiratory control was not affected. Synaptosomal mitochondria would be susceptible to undergo calcium-induced depolarization in 17 months-old mice, while non synaptic mitochondrian would not be affectred by calcium overload. UCP2 was significantly up-regulated in both synaptosomal and submitochondrial membranes from 17-months old mice, compared to young animals. UCP-2 upregulation seems to be a possible mechanism by which mitochondria would be resistant to suffer oxidative damage during aging.
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    Free radical production and antioxidant status in brain cortex non-synaptic mitochondria and synaptosomes at alcohol hangover onset
    (Elsevier, 2017-7) Karadayian, Analía G. ; Malanga, Gabriela ; Czerniczyniec, Analía G. ; Lombardi, Paulina ; Bustamante, Juanita ; Lores-Arnaiz, Silvia
    Alcohol hangover (AH) is the pathophysiological state after a binge-like drinking. We have previously demonstrated that AH induced bioenergetics impairments in a total fresh mitochondrial fraction in brain cortex and cerebellum. The aim of this work was to determine free radical production and antioxidant systems in non-synaptic mitochondria and synaptosomes in control and hangover animals. Superoxide production was not modified in non-synaptic mitochondria while a 17.5% increase was observed in synaptosomes. A similar response was observed for cardiolipin content as no changes were evidenced in non-synaptic mitochondria while a 55% decrease in cardiolipin content was found in synaptosomes. Hydrogen peroxide production was 3-fold increased in non-synaptic mitochondria and 4-fold increased in synaptosomes. In the presence of deprenyl, synaptosomal H2O2 production was 67% decreased in the AH condition. Hydrogen peroxide generation was not affected by deprenyl addition in non-synaptic mitochondria from AH mice. MAO activity was 57% increased in non-synaptic mitochondria and 3-fold increased in synaptosomes. Catalase activity was 40% and 50% decreased in non-synaptic mitochondria and synaptosomes, respectively. Superoxide dismutase was 60% decreased in non-synaptic mitochondria and 80% increased in synaptosomal fractions. On the other hand, GSH (glutathione) content was 43% and 17% decreased in synaptosomes and cytosol. GSH-related enzymes were mostly affected in synaptosomes fractions by AH condition. Acetylcholinesterase activity in synaptosomes was 11% increased due to AH. The present work reveals that AH provokes an imbalance in the cellular redox homeostasis mainly affecting mitochondria present in synaptic terminals.
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    Ketamine effect on intracellular and mitochondrial calcium mobilization
    (Biocell, 2016) Bustamante, Juanita ; Czerniczyniec, Analía G. ; Lores-Arnaiz, Silvia
    The suppressive effects of ketamine on intracellular calcium has been reported in a variety of cells although the mechanisms involved are not well understood. The aim of this work was to evaluate the ketamine effect on the mitochondrial Ca2+ accumulation and the cellular Ca2+ mobilization using FLUO4-AM and flow cytometry. The results showed that mitochondria from ketamine injected animals presented a lower ability to retain calcium at concentrations higher than 20 µM, as compared with controls (saline injected animals). In addition, ketamine showed a significant decreased KCl-induced intracellular calcium concentration. KCl increased calcium influx through cellular depolarization. According to the data presented herein, ketamine presents a clear inhibitory effect on cytosolic Ca2+ transport mechanisms, independently from their action on the calcium channel associated NMDA receptor.
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    Paraoxonase 1 gene polymorphisms and enzyme activities in coronary artery disease and its relationship to serum lipids and glycemia
    (Elsevier, 2016-8-1) Fridman, Osvaldo ; Riviere, Stephanie ; Fuchs, Alicia Graciela ; Potenzoni, Miguel Ángel ; Porcile, Rafael ; Gariglio, Luis Osvaldo
    Objectives: Oxidative stress and inflammation are important processes in development of atherosclerosis. Paraoxonase 1 (PON1) is a bioscavenger enzyme associated with inflammation and oxidative stress. We evaluate the association of two single nucleotide polymorphisms in PON1 gene, and enzyme activities with lipid profile and glycemia. Methods: This case-control study consisted of 126 patients with coronary artery disease (CAD) and 203 healthy controls. PON Q192R and L55M polymorphisms were detected by real-time PCR. Paraoxonase and arylesterase activities were determined spectrophotometrically. Blood glucose, cholesterol, triglycerides, HDL, and LDL were measured. Results: PON1 QR192 polymorphism had a major effect on paraoxonase but no effect on arylesterase serum activities. Paraoxonase activity was higher in RR genotype and lowest in QQ genotype. Paraoxonase and arylesterase activities were higher in LL and lower in MM genotypes of PON1 LM55 polymorphism. RQ and LM variants showed intermediate activities between respective homozygous. Elevated concentrations of triglycerides in cases correlate with QQ variant or the presence of M allele. Glucose levels were elevated in cases with QQ variant or with the presence of M allele. Cholesterol and LDL did not show variations in control and cases with any variant of both polymorphisms. HDL is lower in cases with respect to controls independently of genotypes. All differences were significant with p < 0.05.
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    Phospholipid changes in Rhinella arenarum embryos under different acclimation conditions to copper
    (Elsevier, 2016-10) Herkovits, Jorge ; Fridman, Osvaldo ; Fonovich, Teresa M. ; Pérez-Coll, Cristina S. ; José L., D'eramo
    We report phospholipid changes in Rhinella arenarum embryos after applying three acclimation protocols to copper between 40 and 420 ng L- 1. The lower and higher acclimation treatments resulted in embryos' enhanced resistance to this metal. Phospholipid remodeling activity, evident through arachidonic acid radioactivity incorporation increase in phosphatidylcholine (PC) and sphingomyelin (SPH) fractions, was registered in embryos acclimated to the intermediate exposure condition. Concomitantly, a decrease in phosphatidic acid fraction (PA) was registered in the higher acclimation condition. PC/PE radioactivity ratio increased both for medium and high acclimation conditions from 0.493 in control embryos to 1.378 and 1.032 respectively. Phospholipid changes could be relevant for changes in membrane features associated with low level exposures to copper, preparing the embryo for a higher resistance to this metal. The increased resistance to copper could also be associated with both an increase in metallothioneins concentration, as registered with HPLC in all the acclimation conditions, and an increase in the copper bound to the third fraction of metallothioneins separated by this method. Our results point out that even very low level exposure to copper results in phospholipid metabolism changes that could be relevant for the acclimation phenomena.
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    Response to the letter to the editor : mitochondria isolated from the striatum of the brain exhibit a higher degree of oxidative phosphorylation coupling, which shows that they are not subject to energetic dysfunction upon acute paraquat administration
    (Springer, 2016-9-29) Czerniczyniec, Analía ; Karadayian, Analía G. ; Bustamante, Juanita ; Lores-Arnaiz, Silvia
    In response to criticisms raised by Professor Rendon regarding our original study “Impairment of striatal mitochondrial function by acute paraquat poisoning” (J Bioenerg Biomembr 47:395–408, 2015), we re-evaluated key methodological aspects and data interpretation. Oxygen consumption rates were measured in the absence and presence of KCN (1.3 mM) and diphenyleneiodonium (DPI, 1 µM) to discriminate KCN-sensitive respiration from paraquat redox cycling. Paraquat inhibited state 4 and state 3 KCN-sensitive respiration by 80% and 62%, respectively, while DPI-sensitive oxygen uptake increased 2.2- to 2.3-fold, confirming both respiratory-chain inhibition and redox-cycling contributions. Respiratory control ratios were deliberately omitted for KCN-sensitive data, as they do not accurately reflect mitochondrial viability under these conditions; instead, direct analysis of metabolic states 4 and 3 revealed clear bioenergetic impairment. Submitochondrial membrane preparations were tested for vesicle formation using FCCP (4 µM); no stimulation of NADH-cytochrome c reductase, succinate-cytochrome c reductase, or cytochrome oxidase activities occurred, and paraquat-induced inhibition (27% in complex I–III and 19% in complex IV) persisted unchanged. Rotenone (3 µM) inhibited NADH-cytochrome c reductase by ~80% in both control and paraquat samples, confirming that measured activity was predominantly rotenone-sensitive complex I–III (32% inhibition by paraquat). These additional controls validate our original methodology and support the conclusion that acute paraquat poisoning impairs striatal mitochondrial bioenergetics through direct respiratory-chain inhibition and increased free-radical production.