Elevation of Amino Acids in the Interstitial Space of the Rat Brain following Infusion of Large Neutral Amino and Keto Acids by Microdialysis: Alpha-Ketoisocaproate Infusion

Zielke, H. Ronald; Huang, Y.; Tildón, J. Tyson; Zielke, Carol L.; Baab, Peter J.

doi:10.1159/000111436

Cited by 19 publications

(10 citation statements)

References 8 publications

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“…This hypothesis would be consistent with the elegantly described hypothesis of brain injury in MSUD due to altered bioenergetics, recently put forth by Zinnanti and coworkers [13]. Overall, it remains possible that disturbed glutamate/2-oxoglutarate homeostasis underscores the acute encephalopathy seen in MSUD patients who decompensate [27]. …”

Section: Discussionsupporting

confidence: 85%

Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)

Skvorak

Hager

Arning

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Skvorak and coworkers [1] demonstrated the therapeutic efficacy of HTx in a murine model of iMSUD, confirming significant metabolic improvement and survival. To determine the effect of HTx on extrahepatic organs, we examined the metabolic effects of HTx in brain from iMSUD animals. Amino acid analysis revealed that HTx corrected increased ornithine, partially corrected depleted glutamine, and revealed a trend toward alloisoleucine correction. For amino acid and monoamine neurotransmitters, decreased GABA was partially corrected with HTx, while the L-histidine dipeptide of GABA, homocarnosine, was decreased in iMSUD mice and hypercorrected following HTx. Elevated branched chain amino acids (BCAA; leucine, isoleucine, valine) in MSUD can deplete brain tyrosine and tryptophan (the precursors of monoamine neurotransmitters dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT)) through competition via the large neutral amino acid transporter. HTx corrected decreased DA levels and the DA metabolite, 3-methoxytyramine, and partially corrected the DA intermediate 3,4-dihydroxyphenylacetate (DOPAC) and 5-HT levels, despite normal tyrosine and tryptophan levels in iMSUD mouse brain. We further observed enhanced intracellular turnover of both DA and 5-HT in iMSUD mouse brain, both of which partially corrected with HTx. Our results suggest new pathomechanisms of neurotransmitter metabolism in this disorder and support the therapeutic relevance of HTx in iMSUD mice, while providing proof-of-principle that HTx has corrective potential in extrahepatic organs.

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Section: Discussionsupporting

confidence: 85%

Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)

Skvorak

Hager

Arning

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Competitive large neutral amino acid uptake across the blood-brain barrier. The pattern of large neutral amino acids (LNAAs) in plasma determines their uptake into the brain, mediated by the LAT1 transporter [31]. Influx of each amino acid is strongly affected by the ambient concentration of competing substrates on each side of the membrane.…”

Section: Pathophysiologymentioning

confidence: 99%

Branched-chain ketoacyl dehydrogenase deficiency: Maple syrup disease

Strauss

Morton²

2003

Curr Treat Options Neurol

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Classic maple syrup disease can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. The majority of affected infants that are prospectively managed have good neurodevelopmental outcome; however, acute metabolic intoxication and neurologic deterioration can develop rapidly at any age. Each episode is associated with a risk for cerebral edema, cerebrovascular compromise, and brain herniation. High plasma leucine and, possibly, alpha-ketoisocaproate are the principal neurotoxins in maple syrup disease. Plasma levels rise rapidly in association with net protein catabolism provoked by common infections and injuries. Transient periods of maple syrup disease encephalopathy appear fully reversible, leaving no clinically detectable neurologic sequelae. In contrast, prolonged amino acid imbalance, particularly if occurring during the critical period of brain development, leads to neuronal hypoplasia, a paucity of synapses, and undermyelination. Stagnated maturation and inadequate nutritional maintenance of brain structure have lifelong neurologic and behavioral consequences. Core elements of effective long-term therapy include screening and identification of asymptomatic newborns, frequent plasma amino acid monitoring, careful attention to branched-chain amino acid nurtriture, prevention of cerebral essential amino acid deficiencies, adequate provision of essential omega-3 class fatty acids and micronutrients deficient in commercial formulas, methods for home monitoring of metabolic control, and a commitment to lifelong therapy. Recognizing the risk for acute leucine intoxication depends on anticipating effects of common childhood infection and physiologic stresses on whole body protein turnover. Successful management of metabolic decompensation is based on the use of home sick-day regimens, rapid availability of branched-chain amino acid-free hyperalimentation solutions for hospitalized children, prevention of hyponatremia in patients with leucinosis, and frequent adjustments of intravenous therapies guided by plasma amino acid levels and indices of metabolic and clinical response.

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“…When entering the cell, ␣-KIC can be oxidized and rapidly integrate the TCA cycle to form CO 2 (Bixel and Hamprecht, 1995;Hutson et al, 1998) or be transaminated with glutamate to form ␣-ketoglutarate and leucine (Yudkoff et al, 1996). The newly formed [ 14 C]leucine is massively released into the extracellular space (Zielke et al, 1996). These two pathways most likely contribute to the decrease in the accumulation of radioactivity in intact neurons, which is not the case in vesicles.…”

Section: Transport Of ␣-Kic Into Cortical Neurons Points To a Metabolmentioning

confidence: 99%

“…In neurons, ␣-KIC is actively transaminated (Yudkoff et al, 1994b(Yudkoff et al, , 1996Zielke et al, 1996), increasing the oxidation of glutamate (Zielke et al, 1997). This first step in the catabolism of ␣-KIC is catalyzed by the cytosolic isoform of branched-chain amino acid aminotransferase (BCATc), which is located predominantly in neurons (Hall et al, 1993;Hutson et al, 1998).…”

Section: Transport Of ␣-Kic Into Cortical Neurons Points To a Metabolmentioning

confidence: 99%

Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: Study of the leucine‐glutamate cycle

Dufour

Nałęcz

Nałȩcz

et al. 2001

J of Neuroscience Research

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We suggest that a dysregulation of energy metabolism in the brain of genetic absence epilepsy rats from Strasbourg (GAERS) could create a specific cerebral environment that would favor the expression of spike-and-wave discharges (SWD) in the thalamocortical loop, largely dependent on glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmissions. We tested several aspects of metabolic activity in the brain of GAERS compared to a genetic strain of nonepileptic (NE) rats. Glucose metabolism was higher in all brain regions of GAERS compared to those of NE rats along the whole glycolytic and aerobic pathways, as assessed by regional histochemical measurement of lactate dehydrogenase and cytochrome oxidase activities. Branched-chain amino acids (BCAA) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine, when injected intraperitoneally, increased the number of SWD in GAERS but had only a slight effect on their duration. These data speak in favor of a BCAA- or alpha-KIC-induced change in neuronal excitability. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAA and alpha-KIC, by decreasing glutamatergic neurotransmission, could favor GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS. Finally, the transport of [1-(14)C]alpha-KIC in freshly isolated cortical neurons was lower in GAERS than in NE rats, and this difference was shown to be of metabolic origin. The addition of gabapentin, a specific inhibitor of BCAA transaminase (BCAT), reduced the transport of [1-(14)C]alpha-KIC in GAERS and NE rats to a level that became identical in both strains. This strain-dependent change was not related to a difference in the activity of BCAT, which was identical in GAERS and NE rats. The exact origin of this apparent metabolic dysregulation of energy metabolism in GAERS that could underlie the origin of seizures in that strain remains to be explored further.

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Elevation of Amino Acids in the Interstitial Space of the Rat Brain following Infusion of Large Neutral Amino and Keto Acids by Microdialysis: Alpha-Ketoisocaproate Infusion

Cited by 19 publications

References 8 publications

Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)

Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)

Branched-chain ketoacyl dehydrogenase deficiency: Maple syrup disease

Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: Study of the leucine‐glutamate cycle

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