Physiology and pathophysiology of organic acids in cerebrospinal fluid

Abstract

Concentrations of organic acids in cerebrospinal fluid (CSF) appear to be directly dependent upon their rate of production in the brain. There is evidence that the net release of short-chain monocarboxylic acids from the brain is a major route for removing these products of cerebral metabolism. Concentrations of organic acids in blood and CSF are largely independent of each other. Quantitative reference values for the concentrations of organic acids in CSF and plasma as well as ratios of individual organic acids between CSF and plasma were determined in 35 pairs of samples from paediatric patients. Over 25 organic acids were quantifiable in all or in the majority of CSF and/or plasma specimens (limit of detection 1 mumol/L). There were substantial differences in the CSF/plasma ratios between subgroups of organic acids. Metabolites related to fatty-acid oxidation were present in CSF in substantially less amounts than in plasma. Organic acids related to carbohydrate and energy metabolism and to amino acid degradation were present in CSF in the same amounts as or slightly smaller amounts than in plasma. Finally, some organic acids were found in substantially higher amounts in CSF than in plasma, e.g. glycolate, glycerate, 2,4-dihydroxybutyrate, citrate and isocitrate. Studies of organic acids in CSF and plasma samples are presented from patients with 'cerebral' lactic acidosis, disorders of propionate and methylmalonate metabolism, glutaryl-CoA dehydrogenase deficiency and L-2-hydroxy-glutaric aciduria. It became apparent that derangements of organic acids in the CSF may occur independently of the systemic metabolism. Quantitative organic acid analysis in CSF will yield new information on the pathophysiology in the central nervous system (CNS) of these disorders and may prove necessary for successful monitoring of treatment of organoacidopathies, which present mainly with neurological disease. For example, in glutaryl-CoA dehydrogenase deficiency the urinary excretion of glutarate appears to be an inadequate parameter for monitoring the effect of dietary therapy, without plasma and CSF determinations. In L-2-hydroxyglutaric aciduria the elevation of L-2-hydroxyglutarate was found to be greater in CSF than in plasma. In addition, some other organic acids, glycolate, glycerate, 2,4-dihydroxybutyrate, citrate and isocitrate, were also elevated in the CSF of the patients out of proportion to normal levels in plasma and urine. High concentrations of an unknown compound, which was tentatively identified as 2,4-dihydroxyglutarate, were found in the CSF of patients with L-2-hydroxyglutaric aciduria.(ABSTRACT TRUNCATED AT 400 WORDS)

Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

“…This increase in certain molecules in the CSF, some of which are known to be present in higher concentrations in plasma than in CSF (28)(29)(30)(31), may result from a selective compromise of the bloodbrain or blood-CSF barrier, and we indeed found albumin to be elevated in the CSF of encephalitic animals. However the identification of numerous free fatty acids and lysophospholipids may also reflect increased phospholipases in the SIV-infected brain.…”

“…However, considering fatty acid entry, production, and metabolism in the CNS, the interpretation is likely more complex (31,52). Both diffusion and carrier-mediated transport systems enable blood-born free and esterified fatty acids to enter the brain, and the brain can also synthesize fatty acids.…”

Chronic postnatal administration of methylmalonic acid provokes a decrease of myelin content and ganglioside N-acetylneuraminic acid concentration in cerebrum of young rats

“…Laboratory findings include metabolic acidosis, ketonemia/ketonuria, hypoglycemia, neutropenia, and thrombocytopenia (1). Methylmalonic acidemia was recently included in the group of disorders called cerebral organic acidemias, because the acids can also accumulate in the brain, suggesting that these metabolites may be produced in this organ (2).…”

Propriedades redox de canais de potássio mitocondriais ATP-sensíveis em cérebro de seu efeito neuroprotetor em excitotoxicidade

“…Esses danos ocorrem com maior freqüência em tecido cerebral devido ao maior acúmulo de MMA em decorrência da grande dependência desse tecido em metabolismo aeróbio (Hoffmann et al, 1993(Hoffmann et al, , 1994Baulny et al, 2005). Vários estudos animais in vivo e in vitro demonstram que MMA compromete a produção energética do cérebro (Marisco et al, 2003;Fleck et al, 2004;Royes et al, 2003;Brusque et al, 2002;Calabresi et al, 1998Calabresi et al, , 2001McLaughlin et al, 1998;Wajner e Coelho, 1997;Narasimhan et al, 1996;Toyoshima et al, 1995;Dutra et al, 1993;Wajner et al, 1992).…”

“…Recentemente, tem-se proposto que a abertura do poro de TPM na membrana mitocondrial interna teria um importante papel na cascata de eventos que resulta na morte neuronal em diversos modelos experimentais (Friberg et al, 1998;Fiskum et al, 1999;Nieminen et al, 1996;Schinder et al, 1996;Sawa et al, 1999). Dois eventos da abertura de mitoK ATP podem contribuir para a prevenção de TPM: a diminuição da captação de Ca 2+ (Belisle e Kowaltowski, 2002) e a prevenção da geração de ROS (Ferranti et al, 2003 (Hoffmann et al, 1993;Hoffmann et al, 1994;Baulny et al, 2005). Acredita-se que os danos causados por acidose metilmalônica são devido a uma deficiência do metabolismo energético, semelhante às condições de uma isquemia química ou metabólica (Brusque et al, 2002), sugerindo que estudos mitocondriais podem ser utilizados para prevenir estes danos.…”