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

Simona Colleoni; Anders Asbjørn Jensen; Elisa Landucci; Elena Fumagalli; Paola Conti; Andrea Pinto; Marco De Amici; Domenico E. Pellegrini-Giampietro; Carlo De Micheli; Tiziana Mennini; Marco Gobbi

doi:10.1124/jpet.107.135251

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

Simona Colleoni, Anders Asbjørn Jensen, Elisa Landucci, Elena Fumagalli, Paola Conti, Andrea Pinto, Marco De Amici, Domenico E. Pellegrini-Giampietro, Carlo De Micheli, Tiziana Mennini, Marco Gobbi

23 Citations (Scopus)

Abstract

(+/-)-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.

Original language	English
Journal	Journal of Pharmacology and Experimental Therapeutics
Volume	326
Issue number	2
Pages (from-to)	646-656
Number of pages	11
ISSN	0022-3565
DOIs	https://doi.org/10.1124/jpet.107.135251
Publication status	Published - 2008

Keywords

Animals
Biological Transport
Carboxylic Acids
Cell Line
Cell Survival
Culture Media
Dose-Response Relationship, Drug
Excitatory Amino Acid Transporter 1
Glutamic Acid
Humans
Male
Membrane Potentials
Molecular Structure
Neuroprotective Agents
Oxazoles
Rats
Rats, Inbred Strains
Stereoisomerism
Synaptosomes

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Colleoni, S., Jensen, A. A., Landucci, E., Fumagalli, E., Conti, P., Pinto, A., De Amici, M., Pellegrini-Giampietro, D. E., De Micheli, C., Mennini, T., & Gobbi, M. (2008). 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. Journal of Pharmacology and Experimental Therapeutics, 326(2), 646-656. https://doi.org/10.1124/jpet.107.135251

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. / Colleoni, Simona; Jensen, Anders Asbjørn; Landucci, Elisa et al.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 326, No. 2, 2008, p. 646-656.

Research output: Contribution to journal › Journal article › Research › peer-review

Colleoni, S, Jensen, AA, Landucci, E, Fumagalli, E, Conti, P, Pinto, A, De Amici, M, Pellegrini-Giampietro, DE, De Micheli, C, Mennini, T & Gobbi, M 2008, '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', Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 2, pp. 646-656. https://doi.org/10.1124/jpet.107.135251

Colleoni S, Jensen AA, Landucci E, Fumagalli E, Conti P, Pinto A et al. 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. Journal of Pharmacology and Experimental Therapeutics. 2008;326(2):646-656. doi: 10.1124/jpet.107.135251

Colleoni, Simona ; Jensen, Anders Asbjørn ; Landucci, Elisa et al. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 326, No. 2. pp. 646-656.

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title = "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",

abstract = "(+/-)-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.",

keywords = "Animals, Biological Transport, Carboxylic Acids, Cell Line, Cell Survival, Culture Media, Dose-Response Relationship, Drug, Excitatory Amino Acid Transporter 1, Glutamic Acid, Humans, Male, Membrane Potentials, Molecular Structure, Neuroprotective Agents, Oxazoles, Rats, Rats, Inbred Strains, Stereoisomerism, Synaptosomes",

author = "Simona Colleoni and Jensen, {Anders Asbj{\o}rn} and Elisa Landucci and Elena Fumagalli and Paola Conti and Andrea Pinto and {De Amici}, Marco and Pellegrini-Giampietro, {Domenico E.} and {De Micheli}, Carlo and Tiziana Mennini and Marco Gobbi",

year = "2008",

doi = "10.1124/jpet.107.135251",

language = "English",

volume = "326",

pages = "646--656",

journal = "Journal of Pharmacology and Experimental Therapeutics",

issn = "0022-3565",

publisher = "American Society for Pharmacology and Experimental Therapeutics",

number = "2",

}

TY - JOUR

T1 - 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

AU - Colleoni, Simona

AU - Jensen, Anders Asbjørn

AU - Landucci, Elisa

AU - Fumagalli, Elena

AU - Conti, Paola

AU - Pinto, Andrea

AU - De Amici, Marco

AU - Pellegrini-Giampietro, Domenico E.

AU - De Micheli, Carlo

AU - Mennini, Tiziana

AU - Gobbi, Marco

PY - 2008

Y1 - 2008

N2 - (+/-)-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.

AB - (+/-)-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.

KW - Animals

KW - Biological Transport

KW - Carboxylic Acids

KW - Cell Line

KW - Cell Survival

KW - Culture Media

KW - Dose-Response Relationship, Drug

KW - Excitatory Amino Acid Transporter 1

KW - Glutamic Acid

KW - Humans

KW - Male

KW - Membrane Potentials

KW - Molecular Structure

KW - Neuroprotective Agents

KW - Oxazoles

KW - Rats

KW - Rats, Inbred Strains

KW - Stereoisomerism

KW - Synaptosomes

U2 - 10.1124/jpet.107.135251

DO - 10.1124/jpet.107.135251

M3 - Journal article

C2 - 18451317

SN - 0022-3565

VL - 326

SP - 646

EP - 656

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

IS - 2

ER -