l-Carnitine: therapeutic strategy for metabolic encephalopathy

Kim, C.S.; Dorgan, D.; Roe, Charles R.

doi:10.1016/0006-8993(84)90019-2

Cited by 14 publications

(5 citation statements)

References 17 publications

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“…Accumulation of metabolites of DA and 5-HT in the brain and in the CSF could result from direct toxic effects of octanoate on organic acid transport systems or by competitive inhibition of a common canier by octanoate itself. Octanoic acid is a mitochondrial toxin in both the brain (Parker et al, 1983) and the choroid plexus (Kim et al, 1984(Kim et al, , 1990. We have previously shown both in vitro and in vivo that octanoic acid disrupts the mitochondrial ultrastructure in the choroid plexus (Kim et al, 1984(Kim et al, , 1990 and inhibits the organic anion transport system (Kim et al, 1983b).…”

Section: Discussionmentioning

confidence: 99%

“…Octanoic acid is a mitochondrial toxin in both the brain (Parker et al, 1983) and the choroid plexus (Kim et al, 1984(Kim et al, , 1990. We have previously shown both in vitro and in vivo that octanoic acid disrupts the mitochondrial ultrastructure in the choroid plexus (Kim et al, 1984(Kim et al, , 1990 and inhibits the organic anion transport system (Kim et al, 1983b). Because this transport system in the choroid plexus is responsible for the excretion of monoamine metabolites from the brain to the plasma, the present study provides further evidence for octanoic acid disruption of transport systems for endogenous acid compounds in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…To obtain a more detailed picture of the octanoic acid effect on 5-HIAA clearance in vivo by the choroid plexus [representative of those tissues mediating elimination of organic anions from the brain (Cserr and Van Dyke, 1971;Burns et al, 1976;Rapoport, 1976;Kim et al, 1984Kim et al, , 1987], the clearance of ['4C]5-HIAA from CSF was measured in rabbits by the ventriculocisternal perfusion technique as pre-viously described (Kim et al, 1983a). Artificial CSF containing 1 pM [I4C]5-HIAA with inulin (50 mg/100 ml) as a marker of spinal fluid formation was perfused into the lateral ventricle at a rate of 40 &min for two consecutive 2.5-h periods.…”

Section: In Vivo Ventriculocisternal Perfusion Studies: Radiolabeled mentioning

confidence: 99%

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Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Kim

Roe

Mann

et al. 1992

Journal of Neurochemistry

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Effects of octanoic acid on monoamines and their acidic metabolites in the rat brain were analyzed by HPLC. Octanoic acid (1,000 mg/kg i.p.) elevated homovanillic acid levels by 54% in the caudate and 338% in the hypothalamus but increased 5-hydroxyindoleacetic acid (5-HIAA) levels in both the caudate and the hypothalamus by approximately 50% compared with the control. A lower dose of octanoic acid (500 mg/kg) increased 5-HIAA levels by 29% in the caudate and 20% in the hypothalamus. However, it did not produce any changes in the concentration of homovanillic acid in either the caudate or the hypothalamus. Treatment with octanoic acid also failed to change the level of dopamine, serotonin, and 3,4-dihydroxyphenylacetic acid in the caudate and the hypothalamus. The role of carrier-mediated transport in the clearance of 5-HIAA from the rabbit CSF was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced in the presence of octanoic acid. Because this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of encephalopathy in children with medium-chain acyl-CoA dehydrogenase deficiency who have elevated levels of octanoic acid systematically.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In Vivo Ventriculocisternal Perfusion Studies: Radiolabeled mentioning

confidence: 99%

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Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Kim

Roe

Mann

et al. 1992

Journal of Neurochemistry

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“…However, this animal model appears to be more specific for human MCAD. Recent studies by Kim et al (35) demonstrate that octanoate produces extensive ultrastructural and functional damage to the mitochondria of the choroid plexus. Neither octanoylcarnitine nor L-carnitine produce such ultrastructural abnormalities in this tissue.…”

Section: Mcad Urine ( F a B )mentioning

confidence: 99%

Diagnostic and Therapeutic Implications of Medium-Chain Acylcarnitines in the Medium-Chain Acyl-CoA Dehydrogenase Deficiency

et al. 1985

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“…present in high serum concentration may produce a profound disturbance of brain function (Trauner and Huttenlocher, 1978;Trauner and Adams, 198 1). The mechanism of octanoate-associated encephalopathy is unclear, but available evidence indicates that this fatty acid may disrupt neuronal membrane integrity and uncouple mitochondrial oxidative phosphorylation (Parker et al, 1983;Stanley et al, 1983;Kim et al, 1984;Soboll et al, 1984;Drewes and Leino, 1985). Because octanoate is the primary fatty acid present in milk of lactating rats (Helander and Olivecrona, 1970;Knudsen et al, 1976;Libertini and Smith, 1978), one might expect relatively high levels of this fatty acid in the circulation during the period of postnatal brain development.…”

Section: Discussionmentioning

confidence: 99%

Enzymes of Fatty Acid β‐Oxidation in Developing Brain

Reichmann

Maltese

DeVivo

1988

Journal of Neurochemistry

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Developmental profiles were determined for the activities of eight enzymes involved in fatty acid beta-oxidation in rat brain. The enzymes studied were the palmitoyl-CoA, octanoyl-CoA, butyryl-CoA, glutaryl-CoA, and 3-hydroxyacyl-CoA dehydrogenases, the enoyl-CoA hydratase (crotonase), and the C4- and C10-thiolases. With the exception of the thiolases, all of the activities (expressed on the basis of brain weight) increased during the postnatal period of brain maturation. The activity of octanoyl-CoA dehydrogenase was elevated markedly compared to that of palmitoyl-CoA dehydrogenase at all developmental stages and in all brain regions in the rat. A similar relationship between these enzymes was observed in various regions of adult human brain. Comparisons of the activities of the beta-oxidation enzymes in human brain versus human skeletal muscle and in cultured neural cell lines (neuroblastoma and glioma) versus cultured skin fibroblasts revealed that the elevated activity of octanoyl-CoA dehydrogenase relative to palmitoyl-CoA dehydrogenase was specific to the neural tissues. This relationship was particularly evident when the enzyme activities were normalized to the activity of crotonase. The data support previous findings with radiochemical tracers, indicating that the brain is capable of utilizing fatty acids as substrates for oxidative energy metabolism. The relatively high activity of the medium-chain fatty acyl-CoA dehydrogenase in neural tissue may represent an adaptive mechanism to protect the brain from the known encephalopathic effects of octanoate and other medium-chain fatty acids that readily cross the blood-brain barrier.

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l-Carnitine: therapeutic strategy for metabolic encephalopathy

Cited by 14 publications

References 17 publications

Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Octanoic Acid Produces Accumulation of Monoamine Acidic Metabolites in the Brain: Interaction with Organic Anion Transport at the Choroid Plexus

Diagnostic and Therapeutic Implications of Medium-Chain Acylcarnitines in the Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Enzymes of Fatty Acid β‐Oxidation in Developing Brain

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