| Neuroprotective effects of the novel glutamate transporter inhibitor (-)-3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylic acid, which preferentially inhibits reverse transport (glutamate release) compared with glutamate reuptake. | |
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MedLine Citation:
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PMID: 18451317 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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(+/-)-3-Hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4 -d]-isoxazole-4-carboxylic acid (HIP-A) and (+/-)-3-hydroxy-4,5,6, 6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-6-carboxylic acid (HIP-B) are selective inhibitors of excitatory amino acid transporters (EAATs), as potent as DL-threo-beta-benzyloxyaspartic acid (TBOA). We report here that the active isomers are (-)-HIP-A and (+)-HIP-B, being approximately 150- and 10-fold more potent than the corresponding enantiomers as inhibitors of [3H]aspartate uptake in rat brain synaptosomes and hEAAT1-3-expressing cells. Comparable IC(50) values were found on the three hEAAT subtypes. (-)-HIP-A maintained the remarkable property, previously reported with the racemates, of inhibiting synaptosomal glutamate-induced [3H]D-aspartate release (reverse transport) at concentrations significantly lower than those inhibiting [3H]L-glutamate uptake. New data suggest that the noncompetitive-like interaction described previously is probably the consequence of an insurmountable, long-lasting impairment of EAAT's function. Some minutes of preincubation are required to induce this impairment, the duration of preincubation having more effect on inhibition of glutamate-induced release than of glutamate uptake. In organotypic rat hippocampal slices and mixed mouse brain cortical cultures, TBOA, but not (-)-HIP-A, had toxic effects. Under ischemic conditions, a neuroprotective effect was found with 10 to 30 microM (-)-HIP-A, but not with 10 to 30 microM TBOA or 100 microM (-)-HIP-A. The effect of (-)-HIP-A suggests that, under ischemia, EAATs mediate both release (reverse transport) and uptake of glutamate. The neuroprotection with the lower (-)-HIP-A concentrations may indicate a selective inhibition of the reverse transport confirming the data obtained in synaptosomes. The selective interference with glutamate-induced glutamate release might offer a new strategy for neuroprotective action. |
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Authors:
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Simona Colleoni; Anders A Jensen; Elisa Landucci; Elena Fumagalli; Paola Conti; Andrea Pinto; Marco De Amici; Domenico E Pellegrini-Giampietro; Carlo De Micheli; Tiziana Mennini; Marco Gobbi |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2008-05-01 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 326 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-07-21 Completed Date: 2008-08-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 646-56 Citation Subset: IM |
Affiliation:
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Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Transport Carboxylic Acids / chemistry, pharmacology* Cell Line Cell Survival / drug effects Culture Media Dose-Response Relationship, Drug Excitatory Amino Acid Transporter 1 / antagonists & inhibitors*, biosynthesis Glutamic Acid / metabolism* Humans Male Membrane Potentials / drug effects Molecular Structure Neuroprotective Agents / chemistry, pharmacology* Oxazoles / chemistry, pharmacology* Rats Rats, Inbred Strains Stereoisomerism Synaptosomes / drug effects*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo(3,4-d)isoxazole-6-carboxylic acid; 0/Carboxylic Acids; 0/Culture Media; 0/Excitatory Amino Acid Transporter 1; 0/Neuroprotective Agents; 0/Oxazoles; 0/Slc1a3 protein, rat; 56-86-0/Glutamic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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