Document Detail


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.
MedLine Citation:
PMID:  18451317     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
(+/-)-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.
Authors:
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:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-05-01
Journal Detail:
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:
Created Date:  2008-07-21     Completed Date:  2008-08-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  646-56     Citation Subset:  IM    
Affiliation:
Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
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MeSH Terms
Descriptor/Qualifier:
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:
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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