Disturbance of energy and redox homeostasis and reduction of Na+,K+-ATPase activity provoked by in vivo intracerebral administration of ethylmalonic acid to young rats.

Ethylmalonic acid (EMA) accumulation occurs in various metabolic diseases with neurological manifestation, including short acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy (EE). Since pathophysiological mechanisms responsible for brain damage in these disorders are still poorly understood, we investigated the ex vivo effects of acute intrastriatal administration of EMA on important parameters of energy and redox homeostasis in striatum from young rats. We evaluated CO(2) production from glucose, glucose utilization and lactate production, as well as the activities of the citric acid cycle (CAC) enzymes, the electron transfer chain (ETC) complexes II-IV (oxidative phosphorylation, OXPHOS) and synaptic Na(+),K(+)-ATPase. We also tested the effect of EMA on malondialdehyde (MDA) levels (marker of lipid oxidation) and reduced glutathione (GSH) levels. EMA significantly reduced CO(2) production, increased glucose utilization and lactate production, and reduced the activities of citrate synthase and of complexes II and II-III of the ETC, suggesting an impairment of CAC and OXPHOS. EMA injection also reduced Na(+),K(+)-ATPase activity and GSH concentrations, whereas MDA levels were increased. Furthermore, EMA-induced diminution of Na(+),K(+)-ATPase activity and reduction of GSH levels were prevented, respectively, by the antioxidants melatonin and N-acetylcysteine, indicating that reactive species were involved in these effects. Considering the importance of CAC and ETC for energy production and Na(+),K(+)-ATPase for the maintenance of the cell membrane potential, the present data indicate that EMA compromises mitochondrial homeostasis and neurotransmission in striatum. We presume that these pathomechanisms may be involved to a certain extent in the neurological damage found in patients affected by SCADD and EE.

Chronic postnatal ornithine administration to rats provokes learning deficit in the open field task.

Hyperornithinemia is the biochemical hallmark of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2-5 µmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.

Dual mechanism of brain damage induced in vivo by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

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.

Promotion of lipid and protein oxidative damage in rat brain by ethylmalonic acid.

High concentrations of ethylmalonic acid are found in tissues and biological fluids of patients affected by ethylmalonic encephalopathy, deficiency of short-chain acyl-CoA dehydrogenase activity and other illnesses characterized by developmental delay and neuromuscular symptoms. The pathophysiological mechanisms responsible for the brain damage in these patients are virtually unknown. Therefore, in the present work we investigated the in vitro effect of EMA on oxidative stress parameters in rat cerebral cortex. EMA significantly increased chemiluminescence and thiobarbituric acid-reactive species levels (lipoperoxidation), as well as carbonyl content and oxidation of sulfhydryl groups (protein oxidative damage) and DCFH. EMA also significantly decreased the levels of reduced glutathione (non-enzymatic antioxidant defenses). In contrast, nitrate and nitrite levels were not affected by this short organic acid. It is therefore presumed that oxidative stress may represent a pathomechanism involved in the pathophysiology of the neurologic symptoms manifested by patients affected by disorders in which EMA accumulates.

Glomerular filtration rate measurement and prediction equations.

Chronic kidney disease (CKD) is defined as the presence of kidney damage or a glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) for three or more months. Measurement of serum creatinine is the most commonly used method to evaluated kidney function, but it must be included in formulas to estimate GFR, adjusting for age, gender and ethnicity, such as the Modification of Diet in Renal Disease (MDRD) study equation. The performance of this equation is acceptable for patients with CKD but appears to under-estimate GFR in populations with unknown kidney status. A new formula has been developed recently. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation appears to perform better than the MDRD equation. Cystatin C has been widely evaluated as a marker for GFR and seems to be more sensitive than creatinine. The aim of this review is to discuss the recommendations for detecting CKD, emphasizing the characteristics and limitations of GFR estimating equations and pitfalls in the evaluation of urinary albumin excretion.

[Nutritional evaluation of the cirrhotic patient: an objective, subjective or multicompartmental approach?]. / Avaliação nutricional no paciente cirrótico: uma abordagem objetiva, subjetiva ou multicompartimental?

BACKGROUND: Malnutrition due to liver disease is common and its assessment is difficult. The parameters of nutritional evaluation often used in clinical practice have limited use in cirrhotic patients. Many of the clinical signs of malnutrition are the result of the underlying hepatic disease which tends to confound and alter the nutritional diagnosis. AIM: To present a brief review of the different methods of nutritional evaluation together with their limitations and uses in cirrhotic patients. CONCLUSION: The multicompartmental approach for four compartments was shown to be considerably sensitive in the detection of malnutrition. However the ample use of this method is impaired due to technical difficulties and high costs. The handgrip strength appears to be a simple, cheap and effective alternative to detected malnutrition and risk of malnutrition in these patients. Is the most sensitive method and is able to predict a significant incidence of major complications in undernourished cirrhotic patients.

Avaliação nutricional no paciente cirrótico: uma abordagem objetiva, subjetiva ou multicompartimental? / Nutritional evaluation of the cirrhotic patient: an objective, subjective or multicompartmental approach?

RACIONAL: A desnutrição decorrente da doença hepática é freqüente, porém sua detecção é difícil. Os parâmetros de avaliação nutricional comumente utilizados na prática clínica têm seu uso limitado em pacientes cirróticos. Várias das manifestações clínicas da desnutrição são resultantes da doença hepática, o que tende a confundir e alterar o diagnóstico nutricional. OBJETIVOS: Apresentar uma revisão dos diferentes métodos de avaliação nutricional, bem como suas limitações e/ou aplicações em pacientes cirróticos. CONCLUSAO: Dos métodos apresentados, o modelo de avaliação multicompartimental de quatro compartimentos se mostrou bastante eficiente na detecção de desnutrição. Entretanto, apesar dos bons resultados apresentados, os métodos usados para sua detecção ainda esbarram em dificuldades técnicas e de alto custo. A força de aperto de mão não-dominante (dinamometria) aparece como método alternativo pelo baixo custo, simplicidade e eficiência na detecção de desnutridos ou pacientes em risco de desnutrição. É o método mais sensível por predizer uma incidência significativa de complicações em pacientes cirróticos desnutridos.