Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Abstract Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt...

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Autores principales:	Adam M. Wawro, Chandresh R. Gajera, Steven A. Baker, Robert K. Leśniak, Curt R. Fischer, Nay L. Saw, Mehrdad Shamloo, Thomas J. Montine
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0b1cf771b7094dddbe45b3302eac42de
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spelling	oai:doaj.org-article:0b1cf771b7094dddbe45b3302eac42de2021-12-02T18:02:57ZEnantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior10.1038/s41598-021-87569-12045-2322https://doaj.org/article/0b1cf771b7094dddbe45b3302eac42de2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87569-1https://doaj.org/toc/2045-2322Abstract Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln.Adam M. WawroChandresh R. GajeraSteven A. BakerRobert K. LeśniakCurt R. FischerNay L. SawMehrdad ShamlooThomas J. MontineNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Adam M. Wawro Chandresh R. Gajera Steven A. Baker Robert K. Leśniak Curt R. Fischer Nay L. Saw Mehrdad Shamloo Thomas J. Montine Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
description	Abstract Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-Glu or l-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l-Gln.
format	article
author	Adam M. Wawro Chandresh R. Gajera Steven A. Baker Robert K. Leśniak Curt R. Fischer Nay L. Saw Mehrdad Shamloo Thomas J. Montine
author_facet	Adam M. Wawro Chandresh R. Gajera Steven A. Baker Robert K. Leśniak Curt R. Fischer Nay L. Saw Mehrdad Shamloo Thomas J. Montine
author_sort	Adam M. Wawro
title	Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
title_short	Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
title_full	Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
title_fullStr	Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
title_full_unstemmed	Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
title_sort	enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0b1cf771b7094dddbe45b3302eac42de
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Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

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