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1.
Nutrients ; 9(11)2017 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-29156608

RESUMEN

Polyunsaturated fatty acids and antioxidants are important mediators in the central nervous system. Lipid derivatives may control the production of proinflammatory agents and regulate NF-κB activity, microglial activation, and fatty acid oxidation; on the other hand, antioxidants, such as glutathione and ascorbate, have been shown to signal through transmitter receptors and protect against acute and chronic oxidative stress, modulating the activity of different signaling pathways. Several authors have investigated the role of these nutrients in the brains of the young and the aged in degenerative diseases such as Alzheimer's and Parkinson's, and during brain aging due to adiposity- and physical inactivity-mediated metabolic disturbances, chronic inflammation, and oxidative stress. Through a literature review, we aimed to highlight recent data on the role of adiposity, fatty acids, antioxidants, and physical inactivity in the pathophysiology of the brain and in the molecular mechanisms of senescence. Data indicate the complexity and necessity of endogenous/dietary antioxidants for the maintenance of redox status and the control of neuroglial signaling under stress. Recent studies also indicate that omega-3 and -6 fatty acids act in a competitive manner to generate mediators for energy metabolism, influencing feeding behavior, neural plasticity, and memory during aging. Finding pharmacological or dietary resources that mitigate or prevent neurodegenerative affections continues to be a great challenge and requires additional effort from researchers, clinicians, and nutritionists in the field.


Asunto(s)
Envejecimiento/efectos de los fármacos , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Ejercicio Físico , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-6/farmacología , Adiposidad/efectos de los fármacos , Animales , Encéfalo/fisiología , Dieta , Humanos , Inflamación/prevención & control , Modelos Animales , Sistema Nervioso/efectos de los fármacos , Enfermedades Neurodegenerativas/prevención & control , Estrés Oxidativo/efectos de los fármacos
2.
Brain Res ; 1369: 235-44, 2011 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-21059345

RESUMEN

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by a defect in the mitochondrial ornithine transporter, leading to accumulation of ornithine (Orn), homocitrulline (Hcit) and ammonia. Progressive neurological regression whose pathogenesis is not well established is common in this disease. The present work investigated the in vivo effects of intracerebroventricular administration of Orn and Hcit on important parameters of oxidative stress and energy metabolism in cerebral cortex from young rats. Orn and Hcit significantly increased thiobarbituric acid-reactive substances values and carbonyl formation, indicators of lipid and protein oxidative damage, respectively. Furthermore, N-acetylcysteine and the combination of the free radical scavengers ascorbic acid plus α-tocopherol attenuated the lipid oxidation and totally prevented the protein oxidative damage provoked by Orn and Hcit, suggesting that reactive species were involved in these effects. Hcit, but not Orn administration, also decreased glutathione concentrations, as well as the activity of catalase and glutathione peroxidase, indicating that Hcit provokes a reduction of brain antioxidant defenses. As regards to the parameters of energy metabolism, we verified that Orn and Hcit significantly inhibited the citric acid cycle function (inhibition of CO(2) synthesis from [1-(14)C] acetate), the aerobic glycolytic pathway (reduced CO(2) production from [U-(14)C] glucose) and complex I-III activity of the respiratory chain. Hcit also inhibited the activity of aconitase, an enzyme very susceptible to free radical attack. Taken together, our data indicate that mitochondrial homeostasis is disturbed by Orn and especially by Hcit. It is presumed that the impairment of brain bioenergetics and the oxidative damage induced by these metabolites may possibly contribute to the brain deterioration and neurological symptoms affecting patients with HHH syndrome.


Asunto(s)
Corteza Cerebral/metabolismo , Citrulina/análogos & derivados , Ornitina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Citrulina/administración & dosificación , Citrulina/metabolismo , Citrulina/toxicidad , Hiperamonemia/metabolismo , Hiperamonemia/fisiopatología , Inyecciones Intraventriculares , Peroxidación de Lípido/efectos de los fármacos , Ornitina/administración & dosificación , Ornitina/deficiencia , Ornitina/metabolismo , Ratas , Ratas Wistar , Trastornos Innatos del Ciclo de la Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/fisiopatología
3.
Life Sci ; 87(5-6): 139-46, 2010 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-20540954

RESUMEN

AIMS: In the present work we investigated the in vitro effect of cis-4-decenoic acid, the pathognomonic metabolite of medium-chain acyl-CoA dehydrogenase deficiency, on various parameters of bioenergetic homeostasis in rat brain mitochondria. MAIN METHODS: Respiratory parameters determined by oxygen consumption were evaluated, as well as membrane potential, NAD(P)H content, swelling and cytochrome c release in mitochondrial preparations from rat brain, using glutamate plus malate or succinate as substrates. The activities of citric acid cycle enzymes were also assessed. KEY FINDINGS: cis-4-decenoic acid markedly increased state 4 respiration, whereas state 3 respiration and the respiratory control ratio were decreased. The ADP/O ratio, the mitochondrial membrane potential, the matrix NAD(P)H levels and aconitase activity were also diminished by cis-4-decenoic acid. These data indicate that this fatty acid acts as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor. cis-4-decenoic acid also provoked a marked mitochondrial swelling when either KCl or sucrose was used in the incubation medium and also induced cytochrome c release from mitochondria, suggesting a non-selective permeabilization of the inner mitochondrial membrane. SIGNIFICANCE: It is therefore presumed that impairment of mitochondrial homeostasis provoked by cis-4-decenoic acid may be involved in the brain dysfunction observed in medium-chain acyl-CoA dehydrogenase deficient patients.


Asunto(s)
Encéfalo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos Monoinsaturados/toxicidad , Mitocondrias/efectos de los fármacos , Acil-CoA Deshidrogenasa/deficiencia , Animales , Encéfalo/patología , Citocromos c/efectos de los fármacos , Citocromos c/metabolismo , Homeostasis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/metabolismo , NADP/efectos de los fármacos , NADP/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Wistar
4.
Brain Res ; 1296: 117-26, 2009 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-19703432

RESUMEN

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disorder of fatty acid oxidation in which the affected patients predominantly present high levels of octanoic (OA) and decanoic (DA) acids and their glycine and carnitine by-products in tissues and body fluids. It is clinically characterized by episodic encephalopathic crises with coma and seizures, as well as by progressive neurological involvement, whose pathophysiology is poorly known. In the present work, we investigated the in vitro effects of OA and DA on various parameters of energy homeostasis in mitochondrial preparations from brain of young rats. We found that OA and DA markedly increased state 4 respiration and diminished state 3 respiration as well as the respiratory control ratio, the mitochondrial membrane potential and the matrix NAD(P)H levels. In addition, DA-elicited increase in oxygen consumption in state 4 respiration was partially prevented by atractyloside, indicating the involvement of the adenine nucleotide translocator. OA and DA also reduced ADP/O ratio, CCCP-stimulated respiration and the activities of respiratory chain complexes. The data indicate that the major accumulating fatty acids in MCADD act as uncouplers of oxidative phosphorylation and as metabolic inhibitors. Furthermore, DA, but not OA, provoked a marked mitochondrial swelling and cytochrome c release from mitochondria, reflecting a permeabilization of the inner mitochondrial membrane. Taken together, these data suggest that OA and DA impair brain mitochondrial energy homeostasis that could underlie at least in part the neuropathology of MCADD.


Asunto(s)
Acil-CoA Deshidrogenasa/deficiencia , Encéfalo/fisiología , Caprilatos/metabolismo , Ácidos Decanoicos/metabolismo , Homeostasis/fisiología , Mitocondrias/fisiología , Animales , Atractilósido/farmacología , Encéfalo/efectos de los fármacos , Citocromos c/metabolismo , Transporte de Electrón/efectos de los fármacos , Transporte de Electrón/fisiología , Inhibidores Enzimáticos/farmacología , Ácidos Grasos/metabolismo , Homeostasis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/efectos de los fármacos , Translocasas Mitocondriales de ADP y ATP/antagonistas & inhibidores , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/fisiología , NADP/metabolismo , Consumo de Oxígeno/fisiología , Ratas , Ratas Wistar
5.
Brain Res ; 1291: 102-12, 2009 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-19616520

RESUMEN

Tissue accumulation of ornithine (Orn), homocitrulline (Hcit), ammonia and orotic acid (Oro) is the biochemical hallmark of patients affected by hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a disorder clinically characterized by neurological symptoms, whose pathophysiology is practically unknown. In the present study, we investigated the in vitro effect of Orn, Hcit and Oro on important parameters of energy metabolism in brain of 30-day-old Wistar rats since mitochondrial abnormalities have been observed in the affected patients. We first verified that Orn and Hcit significantly inhibited the citric acid cycle (inhibition of CO(2) synthesis from [1-(14)C] acetate, as well as aconitase and alpha-ketoglutarate dehydrogenase activities), the aerobic glycolytic pathway (reduced CO(2) production from [U-(14)C] glucose) and moderately the electron transfer flow (inhibitory effect on complex I-III). Hcit, but not Orn, was also able to significantly inhibit the mitochondrial creatine kinase activity. Furthermore, this inhibition was prevented by GSH, suggesting a possible role of reactive species oxidizing critical thiol groups of the enzyme. In contrast, the other enzyme activities of the citric acid cycle and of the electron transfer chain, as well as synaptic Na(+),K(+)-ATPase were not altered by either Orn or Hcit at concentrations as high as 5.0 mM. Similarly, Oro did not interfere with any of the tested parameters. Taken together, these data strongly indicate that Orn and Hcit compromise brain energy metabolism homeostasis and Hcit also interferes with cellular ATP transfer and buffering. It is therefore suggested that Orn and especially Hcit may be involved in the neurological damage found in patients affected by HHH syndrome.


Asunto(s)
Corteza Cerebral/metabolismo , Citrulina/análogos & derivados , Citosol/metabolismo , Mitocondrias/metabolismo , Ornitina/metabolismo , Análisis de Varianza , Animales , Corteza Cerebral/efectos de los fármacos , Ciclo del Ácido Cítrico/efectos de los fármacos , Ciclo del Ácido Cítrico/fisiología , Citrulina/metabolismo , Citrulina/farmacología , Creatina Quinasa/metabolismo , Citosol/efectos de los fármacos , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Técnicas In Vitro , Mitocondrias/efectos de los fármacos , Ornitina/farmacología , Ácido Orótico/metabolismo , Ácido Orótico/farmacología , Consumo de Oxígeno/efectos de los fármacos , Ratas , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Espectrofotometría , Membranas Sinápticas/efectos de los fármacos , Membranas Sinápticas/metabolismo
6.
Behav Brain Res ; 197(2): 364-70, 2009 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-18950661

RESUMEN

High concentrations of ethylmalonic acid (EMA) are found in tissues and biological fluids of patients affected by ethylmalonic encephalopathy (EE), as well as by deficiency of short-chain acyl-CoA dehydrogenase (SCAD) activity and other illnesses characterized by developmental delay and other neurological and muscular symptoms. The pathophysiological mechanisms responsible for the brain damage in these patients are virtually unknown. However, they may be due to the neurotoxic actions of EMA. Therefore, in the present work we investigated whether chronic exposure of EMA during early development (from 5th to 28th day of life) could alter the behavioral performance of adult rats in the Morris water maze (MWM) and elevated plus maze tasks. Control rats were treated with saline in the same volumes. We observed that adult rats pretreated with EMA presented impairment in the learning and memory in water maze task spending significantly less time in the training quadrant. However, chronic EMA administration did not affect rat performance in the elevated plus maze tasks, suggesting that anxiety-like behavior was not changed by EMA. We also evaluated the in vitro effect of EMA on lipoperoxidation and on creatine kinase (CK) activity in rat hippocampus and observed that this metabolite induced lipid peroxidation and diminished creatine kinase activity. The results provide evidence that early chronic EMA treatment induces long-lasting spatial behavioral deficit that may be possibly related to a secondary bioenergetics dysfunction and/or increase of free radical production caused by this organic acid.


Asunto(s)
Conducta Exploratoria/efectos de los fármacos , Malonatos/toxicidad , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Ansiedad/inducido químicamente , Ansiedad/fisiopatología , Células Cultivadas , Creatina Quinasa/metabolismo , Conducta Exploratoria/fisiología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones Subcutáneas , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malonatos/administración & dosificación , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Ratas , Ratas Wistar , Espectrofotometría , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de Tiempo
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