| Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD). | |
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MedLine Citation:
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PMID: 19699299 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Skvorak et al. [1] demonstrated the therapeutic efficacy of HTx in a murine model of iMSUD, confirming significant metabolic improvement and survival. To determine the effect of HTx on extrahepatic organs, we examined the metabolic effects of HTx in brain from iMSUD animals. Amino acid analysis revealed that HTx corrected increased ornithine, partially corrected depleted glutamine, and revealed a trend toward alloisoleucine correction. For amino acid and monoamine neurotransmitters, decreased GABA was partially corrected with HTx, while the l-histidine dipeptide of GABA, homocarnosine, was decreased in iMSUD mice and hypercorrected following HTx. Elevated branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in MSUD can deplete brain tyrosine and tryptophan (the precursors of monoamine neurotransmitters, dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT)) through competition via the large neutral amino acid transporter. HTx corrected decreased DA levels and the DA metabolite, 3-methoxytyramine, and partially corrected the DA intermediate 3,4-dihydroxyphenylacetate (DOPAC) and 5-HT levels, despite normal tyrosine and tryptophan levels in iMSUD mouse brain. We further observed enhanced intracellular turnover of both DA and 5-HT in iMSUD mouse brain, both of which partially corrected with HTx. Our results suggest new pathomechanisms of neurotransmitter metabolism in this disorder and support the therapeutic relevance of HTx in iMSUD mice, while providing proof-of-principle that HTx has corrective potential in extrahepatic organs. |
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Authors:
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Kristen J Skvorak; Elizabeth J Hager; Erland Arning; Teodoro Bottiglieri; Harbhajan S Paul; Stephen C Strom; Gregg E Homanics; Qin Sun; Erwin E W Jansen; Cornelis Jakobs; William J Zinnanti; K Michael Gibson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-08-19 |
Journal Detail:
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Title: Biochimica et biophysica acta Volume: 1792 ISSN: 0006-3002 ISO Abbreviation: Biochim. Biophys. Acta Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-09-28 Completed Date: 2009-11-25 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1004-10 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, University of Pittsburgh School of Medicine, USA; Children's Hospital of Pittsburgh of UPMC, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Brain / abnormalities*, metabolism*, pathology Carnosine / analogs & derivatives, metabolism Hepatocytes / transplantation* Humans Liver / pathology Maple Syrup Urine Disease / pathology*, therapy* Mice Models, Biological Neurotransmitter Agents / metabolism gamma-Aminobutyric Acid / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HD 57864/HD/NICHD NIH HHS; HD 58553/HD/NICHD NIH HHS; NS 40270/NS/NINDS NIH HHS; R01 HD058553-01/HD/NICHD NIH HHS; R01 NS040270-08/NS/NINDS NIH HHS; R03 HD057864-01/HD/NICHD NIH HHS; R03 HD057864-02/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Neurotransmitter Agents; 305-84-0/Carnosine; 3650-73-5/homocarnosine; 56-12-2/gamma-Aminobutyric Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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