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Mini Nutritional Assessment May Identify a Dual Pattern of Perturbed Plasma Amino Acids in Patients with Alzheimer's Disease: A Window to Metabolic and Physical Rehabilitation? Nutrients 2020; 12:nu12061845. [PMID: 32575805 PMCID: PMC7353235 DOI: 10.3390/nu12061845] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 06/12/2020] [Accepted: 06/18/2020] [Indexed: 12/14/2022] Open
Abstract
Conflicting results about alterations of plasma amino acid (AA) levels are reported in subjects with Alzheimer’s disease (AD). The current study aimed to provide more homogeneous AA profiles and correlations between AAs and cognitive tests. Venous plasma AAs were measured in 54 fasting patients with AD (37 males, 17 females; 74.63 ± 8.03 yrs; 3.2 ± 1.9 yrs from symptom onset). Seventeen matched subjects without neurodegenerative symptoms (NNDS) served as a control group (C-NNDS). Patients were tested for short-term verbal memory and attention capacity and stratified for nutritional state (Mini Nutritional Assessment, MNA). Compared to C-NNDS, patients exhibited lower plasma levels of aspartic acid and taurine (p < 0.0001) and higher 3-methylhistidine (p < 0.0001), which were independent of patients’ MNA. In comparison to normonourished AD, the patients at risk of and with malnutrition showed a tendency towards lower ratios of Essential AAs/Total AAs, Branched-chain AAs/Total AAs, and Branched-chain AAs/Essential AAs. Serine and histidine were positively correlated with verbal memory and attention capacity deficits, respectively. Total AAs negatively correlated with attention capacity deficits. Stratifying patients with AD for MNA may identify a dual pattern of altered AAs, one due to AD per se and the other linked to nutritional state. Significant correlations were observed between several AAs and cognitive tests.
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Conway ME. Alzheimer's disease: targeting the glutamatergic system. Biogerontology 2020; 21:257-274. [PMID: 32048098 PMCID: PMC7196085 DOI: 10.1007/s10522-020-09860-4] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/29/2020] [Indexed: 12/21/2022]
Abstract
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that causes a progressive decline in memory, language and problem solving. For decades mechanism-based therapies have primarily focused on amyloid β (Aβ) processing and pathways that govern neurofibrillary tangle generation. With the potential exception to Aducanumab, a monotherapy to target Aβ, clinical trials in these areas have been challenging and have failed to demonstrate efficacy. Currently, the prescribed therapies for AD are those that target the cholinesterase and glutamatergic systems that can moderately reduce cognitive decline, dependent on the individual. In the brain, over 40% of neuronal synapses are glutamatergic, where the glutamate level is tightly regulated through metabolite exchange in neuronal, astrocytic and endothelial cells. In AD brain, Aβ can interrupt effective glutamate uptake by astrocytes, which evokes a cascade of events that leads to neuronal swelling, destruction of membrane integrity and ultimately cell death. Much work has focussed on the post-synaptic response with little insight into how glutamate is regulated more broadly in the brain and the influence of anaplerotic pathways that finely tune these mechanisms. The role of blood branched chain amino acids (BCAA) in regulating neurotransmitter profiles under disease conditions also warrant discussion. Here, we review the importance of the branched chain aminotransferase proteins in regulating brain glutamate and the potential consequence of dysregulated metabolism in the context of BCAA or glutamate accumulation. We explore how the reported benefits of BCAA supplementation or restriction in improving cognitive function in other neurological diseases may have potential application in AD. Given that memantine, the glutamate receptor agonist, shows clinical relevance it is now timely to research related pathways, an understanding of which could identify novel approaches to treatment of AD.
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Affiliation(s)
- Myra E Conway
- Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK. .,Faculty of Health and Life Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK.
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He W, Wu G. Metabolism of Amino Acids in the Brain and Their Roles in Regulating Food Intake. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1265:167-185. [PMID: 32761576 DOI: 10.1007/978-3-030-45328-2_10] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Amino acids (AAs) and their metabolites play an important role in neurological health and function. They are not only the building blocks of protein but are also neurotransmitters. In the brain, glutamate and aspartate are the major excitatory neurotransmitters, whereas γ-aminobutyrate (GABA, a metabolite of glutamate) and glycine are the major inhibitory neurotransmitters. Nitric oxide (NO, a metabolite of arginine), H2S (a metabolite of cysteine), serotonin (a metabolite of tryptophan) and histamine (a metabolite of histidine), as well as dopamine and norepinephrine (metabolites of tyrosine) are neurotransmitters to modulate synaptic plasticity, neuronal activity, learning, motor control, motivational behavior, emotion, and executive function. Concentrations of glutamine (a precursor of glutamate and aspartate), branched-chain AAs (precursors of glutamate, glutamine and aspartate), L-serine (a precursor of glycine and D-serine), methionine and phenylalanine in plasma are capable of affecting neurotransmission through the syntheses of glutamate, aspartate, and glycine, as well as the competitive transport of tryptophan and tyrosine across from the blood-brain barrier. Adequate consumption of AAs is crucial to maintain their concentrations and the production of neurotransmitters in the central nervous system. Thus, the content and balance of AAs in diets have a profound impact on food intake by animals. Knowledge of AA transport and metabolism in the brain is beneficial for improving the health and well-being of humans and animals.
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Affiliation(s)
- Wenliang He
- Department of Animal Science, Texas A&M University, College Station, TX, USA
| | - Guoyao Wu
- Department of Animal Science, Texas A&M University, College Station, TX, USA.
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Yudkoff M. Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS. Neurochem Res 2017; 42:10-18. [PMID: 27696119 PMCID: PMC5285401 DOI: 10.1007/s11064-016-2057-z] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/29/2016] [Accepted: 09/01/2016] [Indexed: 01/17/2023]
Abstract
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. Import 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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Affiliation(s)
- Marc Yudkoff
- Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Conway ME, Hutson SM. BCAA Metabolism and NH3 Homeostasis. ADVANCES IN NEUROBIOLOGY 2016; 13:99-132. [DOI: 10.1007/978-3-319-45096-4_5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Valproate Disturbs the Balance Between Branched and Aromatic Amino Acids in Rats. Neurotox Res 2013; 25:358-68. [DOI: 10.1007/s12640-013-9441-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 11/05/2013] [Accepted: 11/06/2013] [Indexed: 10/26/2022]
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Hull J, Hindy ME, Kehoe PG, Chalmers K, Love S, Conway ME. Distribution of the branched chain aminotransferase proteins in the human brain and their role in glutamate regulation. J Neurochem 2012; 123:997-1009. [PMID: 23043456 DOI: 10.1111/jnc.12044] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 08/15/2012] [Accepted: 10/02/2012] [Indexed: 12/16/2022]
Abstract
The branched chain aminotransferase enzymes (BCAT) serve as nitrogen donors for the production of 30% of de novo glutamate synthesis in rat brain. Despite the importance of this major metabolite and excitatory neurotransmitter, the distribution of BCAT proteins in the human brain (hBCAT) remains unreported. We have studied this and report, for the first time, that the mitochondrial isoform, hBCATm is largely confined to vascular endothelial cells, whereas the cytosolic hBCATc is restricted to neurons. The majority of hBCATc-labelled neurons were either GABA-ergic or glutamatergic showing both cell body and axonal staining indicating a role for hBCATc in both glutamate production and glutamate release during excitation. Strong staining in hormone secreting cells suggests a further role for the transaminases in hormone regulation potentially similar to that proposed for insulin secretion. Expression of hBCATm in the endothelial cells of the vasculature demonstrates for the first time that glutamate could be metabolized by aminotranferases in these cells. This has important implications given that the dysregulation of glutamate metabolism, leading to glutamate excitotoxicity, is an important contributor to the pathogenesis of several neurodegenerative conditions, where the role of hBCATm in metabolizing excess glutamate may factor more prominently.
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Affiliation(s)
- Jonathon Hull
- Faculty of Health and Life Sciences, University of the West of England, Bristol, UK
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Vuille-Dit-Bille RN, Ha-Huy R, Stover JF. Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous oxygen saturation in patients with severe traumatic brain injury. Amino Acids 2011; 43:1287-96. [DOI: 10.1007/s00726-011-1202-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Accepted: 12/09/2011] [Indexed: 01/31/2023]
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Murín R, Mohammadi G, Leibfritz D, Hamprecht B. Glial Metabolism of Valine. Neurochem Res 2009; 34:1195-203. [DOI: 10.1007/s11064-008-9895-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2008] [Indexed: 11/29/2022]
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Woods SC, Seeley RJ, Cota D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr 2008; 28:295-311. [PMID: 18429698 DOI: 10.1146/annurev.nutr.28.061807.155505] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
To maintain normal activity, single cells must assure that their energy needs and utilization are continuously matched. Likewise, multicellular organisms must constantly coordinate energy intake and expenditure to maintain energy homeostasis. The brain, and the hypothalamus in particular, plays a critical role in integrating and coordinating several types of signals, including hormones and nutrients, to guarantee such homeostasis. Like single cells, the hypothalamus also profits from intracellular pathways known to work as fuel sensors to maintain energy balance. One such pathway is the mammalian target of rapamycin (mTOR). mTOR integrates different sensory inputs to regulate protein synthesis rates in individual cells, and it has recently been implicated in the central nervous system to regulate food intake and body weight as well. This review provides an overview of the role of hypothalamic intracellular fuel sensors in the overall control of energy balance and discusses the potential contribution of these fuel-sensing mechanisms to the metabolic dysregulation associated with obesity.
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Affiliation(s)
- Stephen C Woods
- Department of Psychiatry, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45237, USA.
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Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study. Arch Phys Med Rehabil 2008; 89:1642-7. [PMID: 18760149 DOI: 10.1016/j.apmr.2008.02.023] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Accepted: 02/26/2008] [Indexed: 01/25/2023]
Abstract
OBJECTIVE To investigate whether supplementation with branched-chain amino acids (BCAAs) may improve recovery of patients with a posttraumatic vegetative or minimally conscious state. DESIGN Patients were randomly assigned to 15 days of intravenous BCAA supplementation (n=22; 19.6g/d) or an isonitrogenous placebo (n=19). SETTING Tertiary care rehabilitation setting. PARTICIPANTS Patients (N=41; 29 men, 12 women; mean age, 49.5+/-21 y) with a posttraumatic vegetative or minimally conscious state, 47+/-24 days after the index traumatic event. INTERVENTION Supplementation with BCAAs. MAIN OUTCOME MEASURE Disability Rating Scale (DRS) as log(10)DRS. RESULTS Fifteen days after admission to the rehabilitation department, the log(10)DRS score improved significantly only in patients who had received BCAAs (log(10)DRS score, 1.365+/-0.08 to 1.294+/-0.05; P<.001), while the log(10)DRS score in the placebo recipients remained virtually unchanged (log(10)DRS score, 1.373+/-0.03 to 1.37+/-0.03; P not significant). The difference in improvement of log(10)DRS score between the 2 groups was highly significant (P<.000). Moreover, 68.2% (n=15) of treated patients achieved a log(10)DRS point score of .477 or higher (3 as geometric mean) that allowed them to exit the vegetative or minimally conscious state. CONCLUSIONS Supplemented BCAAs may improve the recovery from a vegetative or minimally conscious state in patients with posttraumatic vegetative or minimally conscious state.
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García-Espinosa MA, Wallin R, Hutson SM, Sweatt AJ. Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids. J Neurochem 2007; 100:1458-68. [PMID: 17348860 DOI: 10.1111/j.1471-4159.2006.04332.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Transamination of the branched-chain amino acids produces glutamate and branched-chain alpha-ketoacids. The reaction is catalyzed by branched-chain aminotransferase (BCAT), of which there are cytosolic and mitochondrial isoforms (BCATc and BCATm). BCATc accounts for 70% of brain BCAT activity, and contributes at least 30% of the nitrogen required for glutamate synthesis. In previous work, we showed that BCATc is present in the processes of glutamatergic neurons and in cell bodies of GABAergic neurons in hippocampus and cerebellum. Here we show that this metabolic enzyme is expressed throughout the brain and spinal cord, with distinct differences in regional and intracellular patterns of expression. In the cerebral cortex, BCATc is present in GABAergic interneurons and in pyramidal cell axons and proximal dendrites. Axonal labeling for BCATc continues into the corpus callosum and internal capsule. BCATc is expressed by GABAergic neurons in the basal ganglia and by glutamatergic neurons in the hypothalamus, midbrain, brainstem, and dorsal root ganglia. BCATc is also expressed in hypothalamic peptidergic neurons, brainstem serotoninergic neurons, and spinal cord motor neurons. The results indicate that BCATc accumulates in neuronal cell bodies in some regions, while elsewhere it is exported to axons and nerve terminals. The enzyme is in a position to influence pools of glutamate in a variety of neuronal types. BCATc may also provide neurons with sensitivity to nutrient-derived BCAAs, which may be important in regions that control feeding behavior, such as the arcuate nucleus of the hypothalamus, where neurons express high levels of BCATc.
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Affiliation(s)
- María A García-Espinosa
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA
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Muller AP, Rotta LN, Kawano C, Leszczinski DN, Schweigert ID, Londero LG, Gravina FS, da Silveira CKB, de Souza CG, Battu CE, Gonçalves CA, de Souza DO, Perry MLS. Effect of 2-deoxy-D-glucose on aminoacids metabolism in rats' cerebral cortex slices. Neurochem Res 2006; 31:417-22. [PMID: 16733818 DOI: 10.1007/s11064-005-9031-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2005] [Indexed: 10/24/2022]
Abstract
We studied the effect of different concentrations of 2-deoxy-D-glucose on the L-[U-14C]leucine, L-[1-14C]leucine and [1-14C]glycine metabolism in slices of cerebral cortex of 10-day-old rats. 2-deoxy-D-glucose since 0.5 mM concentration has inhibited significantly the protein synthesis from L-[U-14C]leucine and from [1-14C]glycine in relation to the medium containing only Krebs Ringer bicarbonate. Potassium 8.0 mM in incubation medium did not stimulate the protein synthesis compared to the medium containing 2.7 mM, and at 50 mM diminishes more than 2.5 times the protein synthesis compared to the other concentration. Only at the concentration of 5.0 mM, 2-deoxy-D-glucose inhibited the CO2 production and lipid synthesis from L-[U-14C] leucine. This compound did not inhibit either CO2 production, or lipid synthesis from [1-14C]glycine. Lactate at 10 mM and glucose 5.0 mM did not revert the inhibitory effect of 2-deoxy-D-glucose on the protein synthesis from L-[U-14C]leucine. 2-deoxy-D-glucose at 2.0 mM did not show any effect either on CO2 production, or on lipid synthesis from L-[U-14C]lactate 10 mM and glucose 5.0 mM.
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Affiliation(s)
- Alexandre P Muller
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Yamamoto M, Iwasa M, Matsumura K, Nakagawa Y, Fujita N, Kobayashi Y, Kaito M, Takeda K, Adachi Y. Improvement of regional cerebral blood flow after oral intake of branched-chain amino acids in patients with cirrhosis. World J Gastroenterol 2005; 11:6792-9. [PMID: 16425386 PMCID: PMC4725045 DOI: 10.3748/wjg.v11.i43.6792] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of oral intake of branched-chain amino acids (BCAA) on brain perfusion in patients with liver cirrhosis.
METHODS: Single photon emission computed tomography scans were performed in 43 patients with cirrhosis and in 15 age-matched healthy subjects. Twenty-nine out of forty-three patients were randomly treated with either BCAA granules or placebo, and single photon emission computed tomography was performed before and after the treatment. We measured the regional cerebral blood flow values using a three-dimensional stereotaxic region of interest template.
RESULTS: Cirrhotic patients had regions of significant hypoperfusion in the bilateral central (right P = 0.039, P<0.05; left P = 0.006 P<0.01), parietal (right P = 0.018, P<0.05; left P = 0.009, P<0.01), angular (right P = 0.039, P<0.05; left P = 0.008, P<0.01), and left pericallosal segments (P = 0.038 P<0.05) as compared with healthy subjects. A significant increase in cerebral perfusion was observed 70 min after the oral intake of BCAA in the angular (right P = 0.012, P<0.05; left P = 0.049, P<0.05), temporal (right P = 0.012, P<0.05; left P=0.038, P<0.05), pericallosal segments (right P = 0.025, P<0.05; left P = 0.049, P<0.05) and left precentral (P = 0.044, P<0.05), parietal (P = 0.040, P<0.05) and thalamus (P = 0.033, P<0.05). No significant change in perfusion was observed in the placebo group.
CONCLUSION: Administration of BCAA rapidly improves cerebral perfusion.
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Affiliation(s)
- Mika Yamamoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan
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Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, Boschi F, Arcidiaco P, Viglio S. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil 2005; 86:1729-35. [PMID: 16181934 DOI: 10.1016/j.apmr.2005.03.022] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To investigate whether supplementation with branched-chain amino acids (BCAAs) in patients with severe traumatic brain injury (TBI) improves recovery of cognition and influences plasma concentrations of tyrosine and tryptophan, which are precursors of, respectively, catecholamine and serotonin neurotransmitters in the brain. DESIGN Forty patients with TBI were randomly assigned to 15 days of intravenous BCAA supplementation (19.6g/d) (n=20) or an isonitrogenous placebo (n=20). SETTING Tertiary care rehabilitation setting in Italy. PARTICIPANTS Forty men (mean age, 32+/-15 y) with TBI and 20 healthy subjects (controls) matched for age, sex, and sedentary lifestyle. INTERVENTION Supplementation with BCAAs. MAIN OUTCOME MEASURES Disability Rating Scale (DRS) and plasma concentrations of BCAAs, tyrosine, and tryptophan. RESULTS Fifteen days after admission to the rehabilitation department, the DRS score had improved significantly in both the placebo group (P<.05 vs baseline) and in the BCAA-supplemented group (P<.01 vs baseline). The difference between the 2 groups was significant (P<.004). Plasma tyrosine concentration improved in the group given BCAA supplementation, and tryptophan concentration increased in patients receiving placebo. CONCLUSIONS Supplemental BCAAs enhance the retrieval of DRS without causing negative effects on tyrosine and tryptophan concentration.
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Affiliation(s)
- Roberto Aquilani
- Servizio di Fisiopatologia Metabolico-Nutrizionale e Nutrizione Clinica
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Yudkoff M, Daikhin Y, Nissim I, Horyn O, Luhovyy B, Luhovyy B, Lazarow A, Nissim I. Brain amino acid requirements and toxicity: the example of leucine. J Nutr 2005; 135:1531S-8S. [PMID: 15930465 DOI: 10.1093/jn/135.6.1531s] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Glutamic acid is an important excitatory neurotransmitter of the brain. Two key goals of brain amino acid handling are to maintain a very low intrasynaptic concentration of glutamic acid and also to provide the system with precursors from which to synthesize glutamate. The intrasynaptic glutamate level must be kept low to maximize the signal-to-noise ratio upon the release of glutamate from nerve terminals and to minimize the risk of excitotoxicity consequent to excessive glutamatergic stimulation of susceptible neurons. The brain must also provide neurons with a constant supply of glutamate, which both neurons and glia robustly oxidize. The branched-chain amino acids (BCAAs), particularly leucine, play an important role in this regard. Leucine enters the brain from the blood more rapidly than any other amino acid. Astrocytes, which are in close approximation to brain capillaries, probably are the initial site of metabolism of leucine. A mitochondrial branched-chain aminotransferase is very active in these cells. Indeed, from 30 to 50% of all alpha-amino groups of brain glutamate and glutamine are derived from leucine alone. Astrocytes release the cognate ketoacid [alpha-ketoisocaproate (KIC)] to neurons, which have a cytosolic branched-chain aminotransferase that reaminates the KIC to leucine, in the process consuming glutamate and providing a mechanism for the "buffering" of glutamate if concentrations become excessive. In maple syrup urine disease, or a congenital deficiency of branched-chain ketoacid dehydrogenase, the brain concentration of KIC and other branched-chain ketoacids can increase 10- to 20-fold. This leads to a depletion of glutamate and a consequent reduction in the concentration of brain glutamine, aspartate, alanine, and other amino acids. The result is a compromise of energy metabolism because of a failure of the malate-aspartate shuttle and a diminished rate of protein synthesis.
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Affiliation(s)
- Marc Yudkoff
- Children's Hospital of Philadelphia, Division of Child Development, Rehabilitation and Metabolic Disease, Department of Pediatrics, University of Pennsylvania School of Medicine, 19104, USA.
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Sweatt AJ, Garcia-Espinosa MA, Wallin R, Hutson SM. Branched-chain amino acids and neurotransmitter metabolism: expression of cytosolic branched-chain aminotransferase (BCATc) in the cerebellum and hippocampus. J Comp Neurol 2004; 477:360-70. [PMID: 15329886 DOI: 10.1002/cne.20200] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
In the brain, catabolism of the branched-chain amino acids (BCAAs) provides nitrogen for the synthesis of glutamate and glutamine. Glutamate is formed through transfer of an amino group from BCAA to alpha-ketoglutarate in reaction catalyzed by branched-chain aminotransferases (BCAT). There are two isozymes of BCAT: cytosolic BCATc, which is found in the nervous system, ovary, and placenta, and mitochondrial BCATm, which is found in all organs except rat liver. In cell culture systems, BCATc is found only in neurons and developing oligodendrocytes, whereas BCATm is the isoform in astroglia. In this study, we used immunohistochemistry to examine the distribution of BCATc in the rat brain, focusing on the well-known neural architecture of the cerebellum and hippocampus. We show that BCATc is expressed only in neurons in the adult rat brain. In glutamatergic neurons such as granule cells of the cerebellar cortex and of the dentate gyrus, BCATc is localized to axons and nerve terminals. In contrast, in GABAergic neurons such as cerebellar Purkinje cells and hippocampal pyramidal basket cells, BCATc is concentrated in cell bodies. A common function for BCATc in these neurotransmitter systems may be to modulate amounts of glutamate available either for release as neurotransmitter or for use as precursor for synthesis of GABA. Particularly striking in our findings is the strong expression of BCATc in the mossy fiber pathway of the hippocampal formation. This result is discussed in light of the effectiveness of the anticonvulsant drug gabapentin, which is a specific inhibitor of BCATc.
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Affiliation(s)
- Andrew J Sweatt
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
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Izumi T, Kawamura K, Ueda H, Bungo T. Central administration of leucine, but not isoleucine and valine, stimulates feeding behavior in neonatal chicks. Neurosci Lett 2004; 354:166-8. [PMID: 14698464 DOI: 10.1016/j.neulet.2003.09.071] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Branched-chain amino acids (BCAAs) are essential amino acids that play a major role in brain energy metabolism. This study was done to elucidate whether central injection of BCAAs influences feeding behavior in chicks. We found that the intracerebroventricular injection of leucine (200 microg) significantly stimulated food intake in neonatal chicks during 30 min postinjection. Additionally, the starting time of feeding and pecking rhythm after injection were significantly accelerated by leucine. In contrast, isoleucine and valine had no effect on ingestive response during experiment periods. Moreover, a metabolite of leucine (alpha-ketoisocaproic acid) at an equimolar concentration of leucine also did not increase food intake in chicks. These results suggest that leucine induces hyperphagia of neonatal chicks and it may be due to the synthesized glutamate by exogenous leucine.
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Affiliation(s)
- Tomofumi Izumi
- Laboratory of Animal Science, Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama 790-8566, Japan
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19
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Aquilani R, Iadarola P, Boschi F, Pistarini C, Arcidiaco P, Contardi A. Reduced plasma levels of tyrosine, precursor of brain catecholamines, and of essential amino acids in patients with severe traumatic brain injury after rehabilitation11No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors(s) or upon any organization with which the author(s) is/are associated. Arch Phys Med Rehabil 2003; 84:1258-65. [PMID: 13680559 DOI: 10.1016/s0003-9993(03)00148-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To investigate whether levels of plasma tyrosine and tryptophan, precursors of brain catecholamine and serotonin neurotransmitters, respectively, and other essential amino acids (EAA) may return to normal in patients with severe traumatic brain injury (TBI) after 2 months in a hospital rehabilitation center. DESIGN Peripheral plasma concentrations of tyrosine, tryptophan, and other EAAs in subjects with severe TBI, both at admission (44+/-11d postinjury) and at discharge from the center (110+/-15d after acute event) were compared with concentrations in control subjects. SETTING Tertiary care rehabilitation setting in Italy. PARTICIPANTS Ten men (26.6+/-12.6y) with TBI and 6 healthy subjects (controls) matched for age, sex, voluntary loss of body weight, and sedentary lifestyle. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Concentrations of brain neurotransmitter precursor amino acids and of EAA. RESULTS On admission, patients had lower plasma tyrosine, leucine, valine, methionine, and phenylalanine concentrations than did control subjects. The plasma concentrations of tryptophan were similar in the 2 groups. These amino acid abnormalities were still present at discharge. CONCLUSION The levels of plasma tyrosine and many EAA in patients with TBI did not recover by discharge (110+/-15d) from rehabilitation. Plasma tryptophan concentrations were similar in patients and controls.
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Affiliation(s)
- Roberto Aquilani
- Servizio di Fisiopatologia Metabolico-Nutrizionale e Nutrizione Clinica, Fondazione S. Maugeri, Istituto Scientifico di Montescano, Pavia, Italy
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20
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Honegger P, Braissant O, Henry H, Boulat O, Bachmann C, Zurich MG, Pardo B. Alteration of amino acid metabolism in neuronal aggregate cultures exposed to hypoglycaemic conditions. J Neurochem 2002; 81:1141-51. [PMID: 12068063 DOI: 10.1046/j.1471-4159.2002.00888.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The neuronal effects of glucose deficiency on amino acid metabolism was studied on three-dimensional cultures of rat telencephalon neurones. Transient (6 h) exposure of differentiated cultures to low glucose (0.25 mm instead of 25 mm) caused irreversible damage, as judged by the marked decrease in the activities of two neurone-specific enzymes and lactate dehydrogenase, 1 week after the hypoglycemic insult. Quantification of amino acids and ammonia in the culture media supernatants indicated increased amino acid utilization and ammonia production during glucose-deficiency. Measurement of intracellular amino acids showed decreased levels of alanine, glutamine, glutamate and GABA, while aspartate was increased. Added lactate (11 mm) during glucose deficiency largely prevented the changes in amino acid metabolism and ammonia production, and attenuated irreversible damage. Higher media levels of glutamine (4 mm instead of 0.25 mm) during glucose deprivation prevented the decrease of intracellular glutamate and GABA, while it further increased intracellular aspartate, ammonia production and neuronal damage. Both lactate and glutamine were readily oxidized in these neuronal cultures. The present results suggest that in neurones, glucose deficiency enhances amino acid deamination at the expense of transamination reactions. This results in increased ammonia production and neuronal damage.
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Affiliation(s)
- Paul Honegger
- Institute of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland.
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21
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Dufour F, Nalecz KA, Nalecz MJ, Nehlig A. Modulation of absence seizures by branched-chain amino acids: correlation with brain amino acid concentrations. Neurosci Res 2001; 40:255-63. [PMID: 11448517 DOI: 10.1016/s0168-0102(01)00232-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The occurrence of absence seizures might be due to a disturbance of the balance between excitatory and inhibitory neurotransmissions in the thalamo-cortical loop. In this study, we explored the consequences of buffering the glutamate content of brain cells on the occurrence and duration of seizures in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a genetic model of generalized non-convulsive epilepsy. Branched-chain amino acids (BCAAs) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine were repeatedly shown to have a critical role in brain glutamate metabolism. Thus, GAERS were injected by intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) route with these compounds, then the effects on seizures were evaluated on the electroencephalographic recording. We also measured the concentration of amino acids in thalamus and cortex after an i.p. injection of leucine or alpha-KIC. Intracerebroventricular injections of leucine or alpha-KIC did not influence the occurrence of seizures, possibly because the substances reached only the cortex. BCAAs and alpha-KIC, injected intraperitoneally, increased the number of seizures whereas they had only a slight effect on their duration. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAAs and alpha-KIC, by decreasing the effects of glutamatergic neurotransmission could facilitate those of GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS.
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Affiliation(s)
- F Dufour
- INSERM U 398, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg cédex, France
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22
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Hutson SM, Lieth E, LaNoue KF. Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 2001; 131:846S-850S. [PMID: 11238772 DOI: 10.1093/jn/131.3.846s] [Citation(s) in RCA: 118] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
A novel hypothesis for the role of branched-chain amino acids (BCAA) in regulating levels of the major excitatory neurotransmitter glutamate in the central nervous system is described. It is postulated that the branched-chain aminotransferase (BCAT) isoenzymes (mitochondrial BCATm and cytosolic BCATc) are localized in different cell types and operate in series to provide nitrogen for optimal rates of de novo glutamate synthesis. BCAA enter the astrocyte where transamination is catalyzed by BCATm, producing glutamate and branched-chain alpha-keto acids (BCKA). BCKA, which are poorly oxidized in astrocytes, exit and are taken up by neurons. Neuronal BCATc catalyzes transamination of the BCKA with glutamate. The products, BCAA, exit the neuron and return to the astrocyte. The alpha-ketoglutarate product in the neurons may undergo reductive amination to glutamate via neuronal glutamate dehydrogenase. Operation of the shuttle in the proposed direction provides a mechanism for efficient nitrogen transfer between astrocytes and neurons and synthesis of glutamate from astrocyte alpha-ketoglutarate. Evidence in favor of the hypothesis is: 1) The two BCAT isoenzymes appear to be localized separately in the neurons (BCATc) or in the astroglia (BCATm). 2) Inhibition of the shuttle in the direction of glutamate synthesis can be achieved by inhibiting BCATc using the neuroactive drug gabapentin. Although gabapentin does not inhibit BCATm, it does block de novo glutamate synthesis from alpha-ketoglutarate. 3) Conversely, gabapentin stimulates oxidation of glutamate. Inhibition of BCATc may allow BCKA to accumulate in the astroglia, thus facilitating conversion of glutamate to alpha-ketoglutarate.
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Affiliation(s)
- S M Hutson
- Wake Forest University School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
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23
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Bixel M, Shimomura Y, Hutson S, Hamprecht B. Distribution of key enzymes of branched-chain amino acid metabolism in glial and neuronal cells in culture. J Histochem Cytochem 2001; 49:407-18. [PMID: 11181743 DOI: 10.1177/002215540104900314] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Transamination of branched-chain amino acids (BCAAs) catalyzed by the branched chain aminotransferase isoenzymes (BCATs) is believed to play an important role in nitrogen shuttling and excitatory neurotransmitter glutamate metabolism in brain. Recently, we have shown that the mitochondrial isoenzyme (BCATm) is the predominant form found in cultured astrocytes. In this study we used immunocytochemistry to examine the distribution of BCAT isoenzymes in cultured rat neurons and microglial cells. The cytoplasm of neurons displayed intense staining for the cytosolic isoenzyme (BCATc), whereas BCATm staining was not detectable in neurons. In contrast, microglial cells expressed BCATm in high concentration. BCATc appeared to be absent in this cell type. The second and committed step in the BCAA catabolic pathway is oxidative decarboxylation of the alpha-keto acid products of BCAT catalyzed by the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex. Because the presence of BCKD should provide an index of the ability of a cell to oxidize BCAA, we have also immunocytochemically localized BCKD in neuron and glial cell cultures from rat brain. Our results suggest ubiquitous expression of this BCKD enzyme complex in cultured brain cells. BCKD immunoreactivity was detected in neurons and in astroglial and microglial cells. Therefore, the expression of BCAT isoenzymes shows cell-specific localization, which is consistent with the operation of an intercellular nitrogen shuttle between neurons and astroglia. On the other hand, the ubiquitous expression of BCKD suggests that BCAA oxidation can probably take place in all types of brain cells and is most likely regulated by the activity state of BCKD rather than by its cell-specific localization.
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Affiliation(s)
- M Bixel
- Physiologisch-chemisches Institut der Universität, Tübingen, Germany
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24
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Bixel MG, Hamprecht B. Immunocytochemical localization of beta-methylcrotonyl-CoA carboxylase in astroglial cells and neurons in culture. J Neurochem 2000; 74:1059-67. [PMID: 10693937 DOI: 10.1046/j.1471-4159.2000.0741059.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Astroglia-rich primary cultures and brain slices rapidly metabolize branched-chain amino acids (BCAAs), in particular leucine, as energy substrates. To allocate the capacity to degrade leucine oxidatively in neural cells, we have purified beta-methylcrotonyl-CoA carboxylase (beta-MCC) from rat liver as one of the enzymes unique for the irreversible catabolic pathway of leucine. Polyclonal antibodies raised against beta-MCC specifically cross-reacted with both enzyme subunits in liver and brain homogenates. Immunocytochemical examination of astroglia-rich rat primary cultures demonstrated the presence of beta-MCC in astroglial cells, where the enzyme was found to be located in the mitochondria, the same organelle that the mitochondrial isoform of the BCA(A) aminotransferase (BCAT) is located in. This colocalization of the two enzymes supports the hypothesis that mitochondrial BCAT is the isoenzyme that in brain energy metabolism prepares the carbon skeleton of leucine for irreversible degradation in astrocytes. Analysis of neuron-rich primary cultures revealed also that the majority of neurons contained beta-MCC. The presence of beta-MCC in most neurons demonstrates their ability to degrade the alpha-ketoisocaproate that could be provided by neighboring astrocytes or could be generated locally from leucine by the action of the cytosolic isoform of BCAT that is known to occur in neurons.
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Affiliation(s)
- M G Bixel
- Physiologisch-chemisches Institut der Universität Tübingen, Germany
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25
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Govinatzki MT, Velleda LS, Trindade VM, Nagel FM, Bueno D, Perry ML. Amino acid metabolism in rat hippocampus during the period of brain growth spurt. Neurochem Res 1997; 22:23-6. [PMID: 9021757 DOI: 10.1023/a:1027364918315] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We studied protein synthesis, lipid synthesis and CO2 production by oxidation of glycine, alanine and leucine by slices of rat hippocampus during the period of brain growth spurt. The metabolism of the three amino acids decreased with the age of the animals. A major reduction was observed in protein synthesis, which was 4 times higher at 7 days of age than at 21 days of age for all amino acids studied. Glycine oxidation to CO2 was twice as high as alanine oxidation and ten times higher than leucine oxidation. The major pathway of leucine utilization was incorporation into proteins. Glycine was the amino acid that had the highest metabolic rate.
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Affiliation(s)
- M T Govinatzki
- Departmento de Bioquímica, Universidade Federal de Rio Grande do Sul, Porto Alegre, Brazil
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26
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Korein J, Sansaricq C, Kalmijn M, Honig J, Lange B. Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. Int J Neurosci 1994; 79:21-45. [PMID: 7744549 DOI: 10.3109/00207459408986065] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Classical Maple Syrup Urine Disease (MSUD) is a disease of infancy which is an inherited disorder of metabolism of branched-chain amino acids (BCAA). The BCAA are normally transaminated to branched-chain keto acids (BCKA). However, the enzyme required to metabolize the BCKA is deficient, resulting in elevation of both, the BCAA and the BCKA. One of the BCAA (isoleucine) produces a metabolite that causes the urine to smell like maple syrup. The elevations of the BCAA and BCKA are associated with an acute, critical neurotoxic condition often prior to the age of two weeks. The clinical state, the electroencephalogram-(EEG), and plasma BCAA levels were evaluated in 26 patients with classical and variant MSUD. Patients were seen from the time of diagnosis, often within a week after birth, and some were followed clinically for more than 20 years while on specific diet therapy. They were monitored by plasma BCAA (leucine, isoleucine and valine) levels and a total of 101 EEGs were performed during different phases of their illness. During periods of acute metabolic decompensation, there were marked clinical symptoms of neurotoxicity including opisthotonos, seizures, and coma with elevated BCAA plasma levels. The EEGs revealed spikes, polyspikes, spike-wave complexes, triphasic waves, severe slowing and bursts of periodic suppression. Occasionally paradoxical EEG arousal was noted while the patient was lethargic. During asymptomatic periods when the plasma BCAA were at low or normal levels, EEG abnormalities occurred in patients with and without residual neurological deficit. These observations included rolandic sharp waves (comb-like rhythm) which were observed in 7 of 15 patients less than two months of age. Additionally, paroxysmal spike and spike-wave response to photic stimuli were observed in 9 of 17 patients. Loading tests were performed on three patients. Clinical and EEG changes were most marked after leucine. Less dramatic EEG changes also occurred with the other two BCAA loads but without clinical manifestations. Elevation of the appropriate BCAA plasma level occurred after each load. These studies and a review of the literature suggest that one component of the pathophysiological mechanism for the acute neurotoxic effects in this disorder is related to a defect in glutamate, glutamine and gamma-aminobutyric acid (GABA) production. The BCAAs are transaminated to BCKAs. Further metabolism of the BCKAs are blocked because of enzyme deficiency required for decarboxylation.(ABSTRACT TRUNCATED AT 400 WORDS)
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Affiliation(s)
- J Korein
- Department of Neurology, New York University Medical Center, NY 10016, USA
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27
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Jonung T, Jeppsson B, Herlin P, Nobin A, Hultberg B. The effects of ammonia tolerance tests on the cerebrospinal fluid concentrations of amino acids and indoleamines in patients with liver cirrhosis. Scand J Gastroenterol 1990; 25:422-8. [PMID: 1694297 DOI: 10.3109/00365529009095510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
To study the effect of ammonia administration on amino acids and indoleamines in cerebrospinal fluid (CSF) and on amino acids, insulin, and glucagon in plasma in humans with liver cirrhosis, we performed seven ammonia tolerance tests on six patients with stable liver cirrhosis. The grade of encephalopathy was determined by psychometric tests. Only one of the patients had pronounced encephalopathy. The other patients had no or only slight encephalopathy. The plasma concentrations of valine, leucine, isoleucine, phenylalanine, tyrosine, and methionine decreased after the ammonia load, whereas no changes were found in the plasma concentrations of glucagon and insulin. In CSF the concentrations of glutamine, aromatic amino acids, and indoleamines increased only in the patient who had pronounced encephalopathy, whereas no changes were found in the other patients. The effect of an ammonia load on the concentrations of neutral amino acids in CSF in patients with pronounced encephalopathy remains to be demonstrated.
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Affiliation(s)
- T Jonung
- Dept. of Surgery and Chemistry, Lund University, Sweden
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28
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Hawkins RA, Huang SC, Barrio JR, Keen RE, Feng D, Mazziotta JC, Phelps ME. Estimation of local cerebral protein synthesis rates with L-[1-11C]leucine and PET: methods, model, and results in animals and humans. J Cereb Blood Flow Metab 1989; 9:446-60. [PMID: 2786885 DOI: 10.1038/jcbfm.1989.68] [Citation(s) in RCA: 79] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We have estimated the cerebral protein synthesis rates (CPSR) in a series of normal human volunteers and monkeys using L-[1-11C]leucine and positron emission tomography (PET) using a three-compartment model. The model structure, consisting of a tissue precursor, metabolite, and protein compartment, was validated with biochemical assay data obtained in rat studies. The CPSR values estimated in human hemispheres of about 0.5 nmol/min/g agree well with hemispheric estimates in monkeys. The sampling requirements (input function and scanning sequence) for accurate estimates of model parameters were investigated in a series of computer simulation studies.
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Affiliation(s)
- R A Hawkins
- Department of Radiological Sciences, UCLA School of Medicine, Los Angeles, CA 90024
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29
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Murthy CR, Hertz L. Acute effect of ammonia on branched-chain amino acid oxidation and incorporation into proteins in astrocytes and in neurons in primary cultures. J Neurochem 1987; 49:735-41. [PMID: 3612122 DOI: 10.1111/j.1471-4159.1987.tb00955.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
14CO2 production and incorporation of label into proteins from the labeled branched-chain amino acids, leucine, valine, and isoleucine, were determined in primary cultures of neurons and of undifferentiated and differentiated astrocytes from mouse cerebral cortex in the absence and presence of 3 mM ammonium chloride. Production of 14CO2 from [1-14C]leucine and [1-14C]valine was larger than 14CO2 production from [U-14C]leucine and [U-14C]valine in both astrocytes and neurons. In most cases more 14CO2 was produced in astrocytes than in neurons. Incorporation of labeled branched-chain amino acids into proteins varied with the cell type and with the amino acid. Addition of 3 mM ammonium chloride greatly suppressed 14CO2 production from [1-14C]-labeled branched chain amino acids but had little effect on 14CO2 production from [U-14C]-labeled branched-chain amino acids in astrocytes. Ammonium ion, at this concentration, suppressed the incorporation of label from all three branched-chain amino acids into proteins of astrocytes. In contrast, ammonium ion had very little effect on the metabolism (oxidation and incorporation into proteins) of these amino acids in neurons. The possible implications of these findings are discussed, especially regarding whether they signify variations in metabolic fluxes and/or in magnitudes of precursor pools.
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30
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Fernstrom JD, Fernstrom MH, Grubb PE. Twenty-four-hour variations in rat blood and brain levels of the aromatic and branched-chain amino acids: chronic effects of dietary protein content. Metabolism 1987; 36:643-50. [PMID: 3600278 DOI: 10.1016/0026-0495(87)90147-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Groups of young adult, male rats were given free access for 12 weeks to a single diet containing either 12%, 24%, or 40% protein (dry weight). At the end of this time, six rats from each diet group were killed every four hours throughout a single 24-hour period, and blood samples and brains were obtained for quantitation of several of the large neutral amino acids (LNAAs). The blood level of each LNAA varied significantly as a function of time of day (tending to be lower during the day than at night) and as a function of dietary protein content (typically rising as protein intake increased). Except for tyrosine and valine, the serum concentration ratio of each LNAA to the sum of the other LNAA (previously reported to be a good predictor of the competitive uptake of each LNAA into brain) and the brain level of each LNAA showed unremarkable variations with time of day and dietary protein content. In contrast, the serum ratios and brain levels of tyrosine and valine did show notable variations at night as a function of dietary protein intake. Together, the results show that within a chronic physiologic range of protein intakes, the serum ratios and brain levels of several large neutral amino acids, particularly tryptophan, bear no relationship to dietary protein level. Though good correlations between these parameters and protein intake were obtained for valine and tyrosine, their physiologic/metabolic significance, if any, is unknown. In general, the data do not support the broad, unvalidated use of serum LNAA ratios in chronic settings as predictors of brain LNAA levels.
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31
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Fair PH, Balthrop JE, Wade JL, Braddon-Galloway S. In vivo incorporation of [14C]leucine into brain protein of mice treated with methylmercury and thiol complexes of methylmercury. Toxicol Lett 1987; 36:213-20. [PMID: 3590217 DOI: 10.1016/0378-4274(87)90188-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The effect of methylmercury and thiol complexes of methylmercury on inhibition of protein synthesis was evaluated. Mice were injected (i.p.) with the following treatments: methylmercuric chloride, methylmercury-glutathione, methylmercury-cysteinylglycine and control (vehicle) for 10 days. Ten animals from each group were injected with [14C]leucine 90 min prior to death. The brains were removed and the extracted protein was subjected to liquid scintillation analysis. Mice receiving the methylmercury and methylmercury-glutathione treatments exhibited significantly greater weight loss than the control while the methylmercury-cysteinylglycine treatment was not significantly different than the control. Incorporation of [14C]leucine into brain protein was significantly depressed in the methylmercury (81% of control) and the methylmercury-glutathione (79% of control) treatments. Protein synthesis in mice receiving the methylmercury-cysteinylglycine complex although not significantly different than the methylmercury treatments was only 92% of the control mice.
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Hertz L, Murthy CR, Lai JC, Fitzpatrick SM, Cooper AJ. Some metabolic effects of ammonia on astrocytes and neurons in primary cultures. NEUROCHEMICAL PATHOLOGY 1987; 6:97-129. [PMID: 3114685 DOI: 10.1007/bf02833602] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Some metabolic effects on primary cultures of neurons or astrocytes were studied following acute or chronic exposure to pathophysiological concentrations (usually 3 mM) of ammonia. Three parameters were investigated: (1) 14CO2 production from 14C-labeled substrates [glucose, pyruvate, branched-chain amino acids (leucine, valine, isoleucine), and glutamate]; (2) interconversion between glutamate and glutamine; and (3) incorporation of label from labeled branched-chain amino acids into proteins. Neither acute nor chronic exposure to ammonia had any effect on 14CO2 production from [U-14C]glucose in astrocytes and neurons, whereas under certain conditions 14CO2 production from [1-14C]pyruvate in astrocytes was inhibited by ammonia. Production of 14CO2 from [1-14C]branched-chain amino acids was inhibited by acute, but stimulated by chronic, exposure to ammonia (3 mM) in astrocytes, with less effect in neurons. Production of 14CO2 from [1-14C]glutamate in both astrocytes and neurons was inhibited by acute exposure to ammonia. In astrocytes, glutamate levels tended to decrease and glutamine levels tended to increase following acute exposure to ammonia; in neurons, both glutamine and glutamate levels decreased. Protein content (per culture dish) increased in astrocytes but not in neurons, after chronic exposure to ammonia, possibly as a result of enhanced protein synthesis and/or by inhibition of protein degradation.
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Abstract
Epilepsy is an ancient disorder which treatment over the centuries has been guided by preconceptions regarding its origin. The major improvements in epilepsy management came following the discovery of the EEG and the development of seizure suppressing agents. These advances in diagnosis and anticonvulsant therapy have further ingrained the conviction that epilepsy is a disease of neurons. Evidence presented here is intended to support a different point of view which suggests that the metabolic modifications in epileptogenic tissue denote subtle alterations in the anatomical and biochemical relationship between neurons and their glial envelopes. As a result the extracellular environment of these cells contain higher than normal levels of glutamic acid. This creates an unnatural functional connectivity between neurons so that they establish abnormal synchronous activity between them and become hyperexcitable due to the depolarizing milieu. To compensate for these biochemical changes it is suggested that some thought might be given to epilepsy management by metabolic manipulation. The measures should be directed specifically towards improving the ability of glia to remove glutamic acid from the extracellular milieu. Two obvious possibilities are to enhance glial glutamine synthesis and to improve the interstitial "wash-out" of glutamic acid in epileptogenic epicenters. Such a therapy would anticipate to gradually diminish seizure incidence and susceptibility without, however, having a direct action on convulsive episodes per se. The approach must be considered an adjunct to current epilepsy treatment and not a substitute for the use of anticonvulsants.
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Murthy CR, Hertz L. Comparison between acute and chronic effects of ammonia on branched-chain amino acid oxidation and incorporation into protein in primary cultures of astrocytes and of neurons. J Neurosci Res 1987; 17:271-6. [PMID: 3599098 DOI: 10.1002/jnr.490170311] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A comparison was made of acute and chronic effects of ammonia on production of 14CO2 from the [U-14C] labeled branched-chain amino acids (BCAA) leucine, isoleucine, and valine as well as from [1-14C] leucine, and on the incorporation of radioactivity from these amino acids into a perchloric-acid-precipitable protein fraction in astrocytes and neurons in primary cultures. Acute exposure of astrocytes to 3mM ammonium chloride suppressed 14CO2 production from [U-14C] BCAA and especially from [1-14C] leucine. This inhibitory effect was abolished or even reversed [( U-14C] leucine) after chronic exposure to ammonia. Analogously, incorporation of radioactivity into the protein fraction was inhibited after acute exposure but not after chronic exposure of astrocytes to ammonia. The total protein content per culture was increased after chronic exposure. In neurons, production of 14CO2 and incorporation of 14C into proteins were less affected than in astrocytes. These results are discussed in relation to the ability of the two cell types to synthesize glutamine.
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Rossi-Fanelli F, Cascino A, Strom R, Cardelli-Cangiano P, Ceci F, Muscaritoli M, Cangiano C. Amino acids and hepatic encephalopathy. Prog Neurobiol 1987; 28:277-301. [PMID: 2883707 DOI: 10.1016/0301-0082(87)90012-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The consideration of HE and its etiology has undergone a radical turn within the past decade. At present HE is seen in the context of severe metabolic derangements, which failure of the liver, the central biochemical powerhouse of the body, must bring with it. The increased awarenesses on the biochemical mechanisms involved in the pathogenesis of HE have found, step by step, their own place in a complex but consequential mosaic of events, in which amino acid and HE are tightly linked. Clinical and experimental studies are needed to further improve the knowledge in this field, nontheless a certain number of corner-stones can be identified: A profound alteration of the central nervous system neurotransmission is responsible for most, if not all, of the symptoms characterizing HE. The plasma amino acid imbalance observed in cirrhotic patients represents a 'condicio sine qua non' HE may develop. A functional impairment of the amino acid transport systems at the level of the blood-brain barrier seems to play a crucial role in causing deleterious modifications of the synaptic neurotransmission in the central nervous system. The reduction of the brain entry of the "toxic" aromatic amino acids usually obtained by parenteral administration of especially tailored amino acid mixtures is most frequently followed by awakening from HE. In conclusion, most of the results obtained have demonstrated that HE represents a research field in which progresses in the knowledge of some of the pathogenic mechanisms have brought the investigators to new therapeutic approaches which have clearly improved the prognosis of patients suffering from this severe neuropsychiatric syndrome.
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Watanabe A, Shiota T, Takei N, Fujiwara M, Nagashima H. Ammonia detoxification by accelerated oxidation of branched chain amino acids in brains of acute hepatic failure rats. BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY 1986; 35:367-75. [PMID: 3718766 DOI: 10.1016/0885-4505(86)90095-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BCAA aminotransferase and BCKA dehydrogenase activities are increased in the mitochondrial fractions from the brains of hepatic failure rats treated with two-thirds removal of CCl4-injured liver. Cerebral leucine decarboxylation was accelerated, and it well correlated with arterial blood ammonia levels. Elevation of brain ammonia content following an intraperitoneal injection of ammonium acetate to hepatic failure rats could be prevented by intravenous infusion of BCAA. Significantly increased brain glutamic acid, glutamine, and alanine contents were noted. These results suggested that accelerated brain BCAA catabolism in acute hepatic failure rats reduce the neurotoxicity of ammonia by promoting the synthesis of glutamic acid and glutamine from BCAA.
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Ashley DV, Liardon R, Leathwood PD. Breakfast meal composition influences plasma tryptophan to large neutral amino acid ratios of healthy lean young men. J Neural Transm (Vienna) 1985; 63:271-83. [PMID: 4067599 DOI: 10.1007/bf01252031] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The effect of a carbohydrate, a 20% protein, or a carbohydrate +0.3% tryptophan TRP breakfast on plasma large neutral amino acid ratios was studied in 6 healthy men. The carbohydrate-rich meal produced shifts in plasma amino acid concentrations such that plasma TRP/LNAA ratios increased from 0.13 to 0.15 (p less than 0.04) and the protein meal decreased the ratio from 0.14 to 0.11 (p less than 0.04) after 1 hour. Addition of 0.3% TRP to the carbohydrate-rich meal increased plasma TRP/LNAA ratios more than 2-fold. The TRP containing meal was thus the only one likely to influence brain 5-HT synthesis, although the difference between the plasma TRP/LNAA ratios after carbohydrate and protein breakfasts suggests that the brain may distinguish, by synthesizing more or less 5-HT, the composition of breakfast meals.
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Jeppsson B, James JH, Edwards LL, Fischer JE. Relationship of brain glutamine and brain neutral amino acid concentrations after portacaval anastomosis in rats. Eur J Clin Invest 1985; 15:179-87. [PMID: 3930256 DOI: 10.1111/j.1365-2362.1985.tb00165.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Evidence from several sources suggest that blood-brain transport of the large neutral amino acids (NAA) is abnormal in animals with a portacaval anastomosis (PCA) and in patients with liver cirrhosis and portal-systemic shunting and encephalopathy, but the underlying mechanisms are unknown. After PCA, the concentration of glutamine (Gln) in brain is markedly increased as a by-product of cerebral ammonia detoxification, and the rate of efflux of Gln from brain is also increased. The following studies were undertaken to clarify the relationships among plasma and brain concentrations of NAA after PCA in rats and to examine the relationship of brain Gln concentration to plasma and brain NAA concentrations. After PCA plasma phenylalanine, tyrosine and histidine were elevated and leucine, isoleucine and valine were lowered. In brain, phenylalanine, tyrosine, histidine and methionine were markedly elevated after PCA and their concentrations in brain far exceeded the concentrations in plasma. Analyses of single, partial and multiple correlations of plasma NAA ratios expressed as plasma competitor function (PCF), brain NAA and brain Gln showed significant correlations between PCF nd brain NAA in shunted rats. A better correlation was found between brain NAA and brain Gln. Correlation coefficients obtained from multiple correlation analysis equalled or exceeded those obtained in the partial correlation or in the single correlation, suggesting that the effects of PCF and brain Gln on brain NAA were separate and additive. Gln was shown to compete with other NAA for blood brain transport by inhibiting brain 14C phenylalanine uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
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Jessy J, Murthy C. Elevation of transamination of branched chain amino acids in brain in acute ammonia toxicity. Neurochem Int 1985; 7:1027-31. [DOI: 10.1016/0197-0186(85)90151-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/1985] [Accepted: 03/14/1985] [Indexed: 11/30/2022]
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Phelps ME, Barrio JR, Huang SC, Keen RE, Chugani H, Mazziotta JC. Criteria for the tracer kinetic measurement of cerebral protein synthesis in humans with positron emission tomography. Ann Neurol 1984; 15 Suppl:S192-202. [PMID: 6611122 DOI: 10.1002/ana.410150736] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The principles and initial results of the use of PET to measure the local cerebral metabolic rate for protein synthesis ( lCRPS ) in humans are described. The labeling of leucine, phenylalanine, and methionine in the carboxyl position provides a strategy (selective position labeling) for discriminating between the incorporation of these amino acids into proteins and metabolic oxidation. In metabolic oxidation the label is removed from tissue through decarboxylation. The resulting labeled carbon dioxide is diluted by the tissue carbon dioxide pool, cleared from cerebral tissue by blood flow, and subsequently ventilated by the lungs. This approach also provides a plasma input function that is free of other labeled amino acids produced through systemic reactions, such as those that occur for methionine labeled in the methyl group. The measured lCRPS is in good agreement with values determined by Smith and Sokoloff by autoradiographic and biochemical assay techniques, as are the measured kinetic rate constants of bidirectional transport, incorporation into proteins, and metabolism, as determined in monkeys and humans using L-leucine labeled with carbon-11 in position 1 (L-[1-11C]leucine) with PET. The tissue leucine precursor pool exhibits a rapid turnover rate (1.5 to 2 minutes), while the metabolic pathway has a half-time (about 18 minutes) that is close to the radioactive half-life of carbon-11. The dietary state was found to affect the branching ratio of lCRPS /metabolism, with a fasted value of 0.4 and carbohydrate feed values ranging up to 1.7. The principle of the method appears sound, and a first-order model provides good fits to data, but much more work is required to determine and validate the model structure and to optimize the study conditions and estimation criteria.
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Affiliation(s)
- L S Eriksson
- Departments of Medicine and Clinical Physiology, Karolinska Institute and Huddinge Hospital, S-141 86 Stockholm, Sweden
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Abumrad NN, Rabin D, Wise KL, Lacy WW. The disposal of an intravenously administered amino acid load across the human forearm. Metabolism 1982; 31:463-70. [PMID: 7043179 DOI: 10.1016/0026-0495(82)90235-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Abumrad NN, Robinson RP, Gooch BR, Lacy WW. The effect of leucine infusion on substrate flux across the human forearm. J Surg Res 1982; 32:453-63. [PMID: 7087433 DOI: 10.1016/0022-4804(82)90126-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Rao TI, Rao GN, Swamy M, Sadasivudu B. Studies on metabolism of branched chain amino acids in brain and other tissues of rat with special reference to leucine. J Neurosci Res 1982; 7:387-95. [PMID: 7143488 DOI: 10.1002/jnr.490070404] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Leucine aminotransferase (EC 2.6.1.6) and 2-oxoisocaproate dehydrogenase (EC 1.2.4.3) were studied in rat cerebral cortex, cerebellum, brain stem, liver, and muscle in normal and animals starved for 48 hours. In the brain, leucine aminotransferase, valine aminotransferase, and 2-oxoisocaproate dehydrogenase showed a significant increase in starvation only in cerebellum while there was increase in 2-oxoisocaproate dehydrogenase in cerebral cortex only. A significantly high increase in the activity of 2-oxoisocaproate dehydrogenase was observed in muscle in starvation. A significant decrease in the activity of leucine aminotransferase was observed in liver in starvation. The increase in the activity of 2-oxoisocaproate dehydrogenase in muscle and a decrease in the activity of leucine aminotransferase in liver in starvation indicate that the leucine is predominantly metabolized in extra hepatic tissues particularly in muscle. As a result of intraperitoneal administration of 2 ml of leucine (5 mM), a significant increase in 2-oxoisocaproate dehydrogenase occurred in cerebral cortex, liver, and muscle while a profound increase in the activity of glutamate dehydrogenase (EC 1.4.1.2) was observed in all the brain regions and liver under these conditions. A significant increase in the content of glutamic acid, alanine, and GABA was observed in all the three regions of the brain after the administration of leucine. A significant increase in the content of glutamine was observed only in the cerebellum and cerebral cortex after leucine administration. These results indicate that leucine in brain might contribute to the formation of glutamate, not only by transamination, but also by promoting glutamate dehydrogenase activity. Thus, there is a change in the metabolism of glutamate family of amino acids and energy depletion. These results are discussed in relation to the brain function.
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Viña JR, Williamson DH. Effects of lactation on L-leucine metabolism in the rat. Studies in vivo and in vitro. Biochem J 1981; 194:941-7. [PMID: 7030319 PMCID: PMC1162831 DOI: 10.1042/bj1940941] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
1. The turnover rate of L-[1-14C]leucine was increased by 35% in lactating rats compared with virgin rats. Starvation or removal of pups (24 h) returned the value to that of the virgin rat. 2. Incorporation of L-[U-14C]leucine into lipid and protein of mammary glands of lactating rats in vivo increased 7-fold and 6-fold respectively compared with glands of virgin rats. Lactation caused no change in the incorporation of L-[U-14C]leucine into hepatic lipid and protein. 3. The production of 14CO2 from L[l-14C]leucine (in the presence of glucose) was similar in isolated acini from glands of fed (chow) and starved lactating rats. Feeding with a 'cafeteria' diet caused a slight decrease, and removal of pups a large decrease, in the oxidative decarboxylation of leucine. 4. Oxidation of L-[2-14C]leucine to 14CO2 was increased about 3-fold in acini from starved lactating rats or lactating rats fed on a 'cafeteria' diet compared with rats fed on a chow diet. Insulin decreased the formation of 14CO2 in all three situations. 5. Incorporation of L-[U-14C]- and [2-14C]-leucine into lipid was decreased in acini from starved lactating rats and lactating rats fed on a 'cafeteria' diet. Insulin tended to increase the conversion of [2-14C]leucine into lipid, but this was significant only in the case of the acini from 'cafeteria'-fed rats. 6. Experiments with (-)-hydroxycitrate indicate that the major route for conversion of leucine carbon into lipid in acini is via citrate translocation from the mitochondria. 7. The physiological implications of these findings are discussed.
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Abstract
An understanding of the mechanisms of transport of circulating nutrients and hormones through the brain capillary wall, i. e., the blood-brain barrier, is important because the availability in brain of these substances influences a number of cerebral metabolic pathways. For example, the utilization by brain of glucose, ketone bodies and branched chain amino acids or the production of monoamines, acetylcholine, carnosine, and nucleosides may under certain conditions be influenced by BBB transport of circulating precursor nutrients. Steroid and thyroid hormones readily traverse the BBB via lipid-mediation and carrier-mediation, respectively. Although the steroid and thyroid hormones are tightly bound by plasma proteins, protein-bound hormone, not the free (dialyzable) moiety, is the major plasma fraction transported through the BBB. With regard to circulating peptides, the available evidence indicates peptides rapidly distribute into brain interstitial space of the circumventricular organs of brain, i. e., about six small regions around the ventricles which lack a BBB. Conversely, the absence of peptide carriers in the BBB prevents the rapid distribution of peptides into the vast majority of brain interstitial or synaptic spaces. However, recent studies indicate that some peptides, e. g., insulin, may bind specific receptors on the blood side of the BBB and thereby transmit messages to cells on the brain side of the BBB, without the peptide traversing the capillary wall.
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Affiliation(s)
- W M Pardridge
- Department of Medicine, Division of Endocrinology and Metabolism, UCLA School of Medicine, Los Angeles, California, USA
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Peterson RG, Baughman S, Scheidler DM. Incorporation of fucose and leucine into PNS myelin proteins in nerves undergoing early Wallerian degeneration. Neurochem Res 1981; 6:213-23. [PMID: 7242779 DOI: 10.1007/bf00964838] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The simultaneous incorporation of [3H]fucose and [1-14C]leucine into normal rat sciatic nerve was examined using an in vitro incubation model. A linear rate of protein precursor uptake was found in purified myelin protein over 1/2-6 hr of incubation utilizing a supplemented medium containing amino acids. This model was then used to examine myelin protein synthesis in nerves undergoing degeneration at 1-4 days following a crush injury. Data showed a statistically significant decrease in the ratio of fucose to leucine at 2, 3, and 4 days of degeneration, which was the consequence of a significant increase in leucine uptake. These results, plus substantial protein recovery in axotomized nerves, are indicative of active synthesis of proteins that purify with myelin during early Wallerian degeneration.
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Galim EB, Hruska K, Bier DM, Matthews DE, Haymond MW. Branched-chain amino acid nitrogen transfer to alamine in vivo in dogs. Direct isotopic determination with [15N]leucine. J Clin Invest 1980; 66:1295-304. [PMID: 7440716 PMCID: PMC371614 DOI: 10.1172/jci109981] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
To investigate the contribution of branched-chain amino acids as a nitrogen source for alanine in vivo, dogs were infused with l-[(15)N]leucine, l-[U-(14)C]leucine, l-[2,3,3,3-(2)H(4)]alanine, and d-[6,6-(2)H(2)]-glucose. (14)C and (15)N isotopic equilibrium in plasma leucine, and deuterium enrichment in arterial and femoral plasma glucose and alanine were achieved within 3 h of initiation of the respective isotope infusion in all animals. The average flux of leucine determined by [(15)N]leucine was 5.4 mumol.kg(-1).min(-1), whereas using [(14)C]leucine it was 3.7 mumol.kg(-1).min(-1). Turnover rates for alanine and glucose were 11.0 and 17.2 mumol.kg(-1).min(-1), respectively.[(15)N]alanine was detected as early as 30 min, but nitrogen isotopic equilibrium in alanine was not achieved until 6 h. The absolute rate of leucine nitrogen transfer to alanine was 1.92 mumol.kg(-1).min(-1), which represented 41-73% (mean 53%) of leucine's nitrogen and 15-20% (mean 18%) of alanine's nitrogen. Fractional extraction of alanine and leucine by the dog hindlimb was 35 and 24%, respectively. Average net alanine balance was -6.7 mumol.leg(-1).min(-1), reflecting a release rate (17.4 mumol.kg(-1).min(-1)) that exceeded the rate of uptake (10.8 mumol.leg(-1).min(-1)). Of the leucine taken up by the hindlimb, 34% transferred its nitrogen to alanine and 8% was oxidized to CO(2). Since the latter value reflects transamination as well as irreversible catabolism, the nitrogen derived from the oxidation of leucine by the hindlimb could account for only 25% of the observed (15)N incorporation into alanine. The significantly faster flux of leucine nitrogen when compared with leucine carbon suggests significant recycling of the leucine alpha-ketoacid. These studies demonstrate that leucine is a major donor of nitrogen to circulating alanine in vivo.
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Wiggins RC, Fuller GN, Bell ME. Incorporation of leucine metabolites into brain and sciatic nerve myelin. J Neurochem 1979; 32:1579-82. [PMID: 438825 DOI: 10.1111/j.1471-4159.1979.tb11102.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Palaiologos G, Koivisto VA, Felig P. Interaction of leucine, glucose, and ketone metabolism in rat brain in vitro. J Neurochem 1979; 32:67-72. [PMID: 759586 DOI: 10.1111/j.1471-4159.1979.tb04510.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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