Transport of α-Ketoisocaproate in Rat Cerebral Cortical Neurons

Mac, Magdalena; Nehlig, Astrid; Nałȩcz, Maciej J.; Nałęcz, Katarzyna A.

doi:10.1006/abbi.2000.1724

Cited by 12 publications

(8 citation statements)

References 49 publications

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“…This might be explained by the much higher K m of Phe for the LAT-1 as compared to the K m values for the BCAAs. Some of these differences in metabolic neuropathology likely relate to accumulation of the BCAA ketoacids in msud mice (and patients), especially 2-oxoisocaproic acid, which is expected to gain brain access on the monocarboxylate transporter [22]. The preceding observations suggest that pharmacological intervention in PKU and MSUD, targeting restriction of the offending amino acid from entry into the brain, will require quite different approaches.…”

Section: Discussionmentioning

confidence: 99%

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pahenu2 mice: Preliminary findings

Vogel

Arning

Wasek

et al. 2013

Molecular Genetics and Metabolism

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Background Our laboratory seeks a pharmacotherapeutic intervention for PKU that utilizes non-physiological amino acids (NPAAs) to block the accumulation of phenylalanine (Phe) in the brain. In previous studies (Vogel et al. 2013), methylation of the amino group of 2-aminoisobutyrate (AIB) provided an enhanced degree of selectivity for Phe restriction into the brain of Pahenu2 mice in comparison to unmethylated AIB, leading to the hypothesis that 2-(methylamino)alkanoic acid analogs of AIB might represent targeted inhibitors of Phe accretion into the brain. Methods Pahenu2 and control mice were intraperitoneally administered (500–750 mg/kg body weight, once daily; standard 19% protein diet) AIB, methyl AIB (MAIB), isovaline, and two MAIB analogs, 2-methyl-2-(methylamino)butanoic (MeVal) and 3-methyl-2-(methylamino)pentanoic (MePent) acids for one week, followed by brain and blood isolation for amino acid analyses using UPLC. Results In the brain, AIB significantly reduced Phe accretion in Pahenu2 mice, while MeVal significantly improved glutamine and aspartic acids. Four of five test compounds improved brain threonine and arginine levels. AIB, MAIB and IsoVal significantly reduced blood Phe, with no effect of any drug intervention on other sera amino acids. Conclusions Further evaluation of AIB and the 2-(methylamino)alkanoic acids as inhibitors of brain Phe accumulation in Pahenu2 mice is warranted, with more detailed evaluations of route of administration, combinatorial intervention, and detailed toxicity studies.

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Section: Discussionmentioning

confidence: 99%

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pahenu2 mice: Preliminary findings

Vogel

Arning

Wasek

et al. 2013

Molecular Genetics and Metabolism

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“…Several lines of evidence suggest that branched-chain amino acids and ketoacids also could be participants in cycle(s) which facilitate movement of N between astrocytes and neurons: (a) These compounds are swiftly transported into brain, thereby establishing a route of efficient articulation between brain and the peripheral circulation; (b) As noted above, the enzymes mediating transamination of branched-chain amino acids/ketoacids display a rigorous anatomic and subcellular (mitochondrial vs cytosolic) distribution in neurons and astrocytes, suggesting the possibility of differential function in either cell type and/or organelle; (c) Neither branched-chain amino acids nor the cognate ketoacids evoke neuronal depolarization, indicating that these compounds can be safely “trafficked” within the CNS; (d) Transport systems for both these amino acids and the ketoacids are present on the surface of both neurons and astrocytes (Brookes et al, 1992; 1993; Broer et al, 1994; Tan et al, 1987; 1988; Rao and Murthy, 1994; Rao et al, 1995; Yudkoff et al, 1996; Mac et al, 2000). …”

Section: Branched-chain Amino Acids As a Source Of Brain Glutamate Nmentioning

confidence: 99%

“…Metabolism is initiated in astrocytes, where mitochondrial branched-chain amino acid transaminase (BCATm) forms α-ketoisocaproate (KIC) and glutamate. The ketoacid is released to neurons, which transport this compound (Mac et al, 2000) and readily convert it back to glutamate (Yudkoff et al, 1996), in the process consuming the latter compound. The leucine formed by “reverse” transamination then can be restored to astrocytes, thereby completing the cycle.…”

Section: Branched-chain Amino Acids As a Source Of Brain Glutamate Nmentioning

confidence: 99%

“…(d) The rate of brain transamination of branched-chain amino acids greatly exceeds the rate of their oxidation (Shambaugh and Koehler, 1983), indicating that brain has ready access to a steady supply of the ketocids. (e) Neurons are capable of transporting the ketoacids (Mac et al, 2000). (f) Transamination can proceed in either the “forward” or “reverse” direction, depending upon the relative concentration of the reactants.…”

Section: Branched-chain Amino Acids As a Source Of Brain Glutamate Nmentioning

confidence: 99%

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Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS

Yudkoff

2016

Neurochem Res

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Glutamatergic neurotransmission entails a tonic loss of glutamate from nerve endings into the synapse. Replacement of neuronal glutamate is essential in order to avoid depletion of the internal pool. In brain this occurs primarily via the glutamate-glutamine cycle, which invokes astrocytic synthesis of glutamine and hydrolysis of this amino acid via neuronal phosphate-dependent glutaminase. This cycle maintains constancy of internal pools, but it does not provide a mechanism for inevitable losses of glutamate N from brain. Importation of glutamine or glutamate from blood does not occur to any appreciable extent. However, the branched-chain amino acids (BCAA) cross the blood-brain barrier swiftly. The brain possesses abundant branched-chain amino acid transaminase activity which replenishes brain glutamate and also generates branched-chain ketoacids. It seems probable that the branched-chain amino acids and ketoacids participate in a “glutamate-BCAA cycle” which involves shuttling of branched-chain amino acids and ketoacids between astrocytes and neurons. This mechanism not only supports the synthesis of glutamate, it also may constitute a mechanism by which high (and potentially toxic) concentrations of glutamate can be avoided by the re-amination of branched-chain ketoacids.

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“…White matter and pial membranes were carefully discarded, and cortical cells were dispersed at 37°C by dispase digestion. Cerebral cortical neurons were isolated from GAERS and NE rat brains by using spinning, filtrating, and density gradient techniques (with dextran), according to techniques previously described in detail (Wawrzenczyk et al, 1995;Mac et al, 2000). The integrity of the cells was controlled by means of the trypan blue test (0.5% in saline).…”

Section: Accumulation Of ␣-Kic In Acutely Isolated Cortical Neuronsmentioning

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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Transport of α-Ketoisocaproate in Rat Cerebral Cortical Neurons

Cited by 12 publications

References 49 publications

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pahenu2 mice: Preliminary findings

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pahenu2 mice: Preliminary findings

Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS

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

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