Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction

Autores
Lenz, Q.F.; Arroyo, Daniela Soledad; Temp, F.R.; Poersch, A.B.; Masson, C.J.; Jesse, A.C.; Marafiga, J.R.; Reschke, C.R.; Iribarren, Pablo; Mello, C.F.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Current evidence suggests that inflammation plays a role in the pathophysiology of seizures. In line with this view, selected pro-inflammatory arachidonic acid derivatives have been reported to facilitate seizures. Kainate-induced seizures are accompanied by leukotriene formation, and are reduced by inhibitors of LOX/COX pathway. Moreover, LTD4 receptor blockade and LTD4 synthesis inhibition suppress pentylenetetrazol (PTZ)-induced kindling and pilocarpine-induced recurrent seizures. Although there is convincing evidence supporting that blood–brain-barrier (BBB) dysfunction facilitates seizures, no study has investigated whether the anticonvulsant effect of montelukast is associated with its ability to maintain BBB integrity. In this study we investigated whether montelukast and other CysLT receptor antagonists decrease PTZ-induced seizures, as well as whether these antagonists preserve BBB during PTZ-induced seizures. Adult male albino Swiss mice were stereotaxically implanted with a cannula into the right lateral ventricle, and two electrodes were placed over the parietal cortex along with a ground lead positioned over the nasal sinus for electroencephalography (EEG) recording. The effects of montelukast (0.03 or 0.3 μmol/1 μL, i.c.v.), pranlukast (1 or 3 μmol/1 μL, i.c.v.), Bay u-9773 (0.3, 3 or 30 nmol/1 μL, i.c.v.), in the presence or absence of the agonist LTD4 (0.2, 2, 6 or 20 pmol/1 μL, i.c.v.), on PTZ (1.8 μmol/2 μL)-induced seizures and BBB permeability disruption were determined. The animals were injected with the antagonists, agonist or vehicle 30 min before PTZ, and monitored for additional 30 min for the appearance of seizures by electrographic and behavioral methods. BBB permeability was assessed by sodium fluorescein method and by confocal microscopy for CD45 and IgG immunoreactivity. Bay-u9973 (3 and 30 nmol), montelukast (0.03 and 0.3 μmol) and pranlukast (1 and 3 μmol), increased the latency to generalized seizures and decreased the mean amplitude of EEG recordings during seizures. LTD4 (0.2 and 2 pmol) reverted the anticonvulsant effect of montelukast (0.3 μmol). Montelukast (0.03 and 0.3 μmol) prevented PTZ-induced BBB disruption, an effect that was reversed by LTD4 at the dose of 6 pmol, but not at the doses 0.2 and 2 pmol. Moreover, the doses of LTD4 (0.2 and 2 pmol) that reverted the effect of montelukast on seizures did not alter montelukast-induced protection of BBB, dissociating BBB protection and anticonvulsant activity. Confocal microscopy analysis revealed that 1. PTZ increased the number of CD45+ and double-immunofluorescence staining for CD45 and IgG cells in the cerebral cortex, indicating BBB leakage with leukocyte infiltration; 2. while LTD4 (6 pmol) potentiated, montelukast decreased the effect of PTZ on leukocyte migration and BBB, assessed by double-immunofluorescence staining for CD45 and IgG cells in the cannulated hemisphere. Our data do not allow us ruling out that mechanisms unrelated and related to BBB protection may co-exist, resulting in decreased seizure susceptibility by montelukast. Notwithstanding, they suggest that CysLT1 receptors may be a suitable target for anticonvulsant development.
Fil: Lenz, Q.F.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Temp, F.R.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Poersch, A.B.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Masson, C.J.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Jesse, A.C.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Marafiga, J.R.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Reschke, C.R.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Mello, C.F.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Materia
Leukotrienes
Pentylenetetrazol
Seizure
Cyslt1r
Montelukast
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/31960
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/31960
network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunctionLenz, Q.F.Arroyo, Daniela SoledadTemp, F.R.Poersch, A.B.Masson, C.J.Jesse, A.C.Marafiga, J.R.Reschke, C.R.Iribarren, PabloMello, C.F.LeukotrienesPentylenetetrazolSeizureCyslt1rMontelukasthttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Current evidence suggests that inflammation plays a role in the pathophysiology of seizures. In line with this view, selected pro-inflammatory arachidonic acid derivatives have been reported to facilitate seizures. Kainate-induced seizures are accompanied by leukotriene formation, and are reduced by inhibitors of LOX/COX pathway. Moreover, LTD4 receptor blockade and LTD4 synthesis inhibition suppress pentylenetetrazol (PTZ)-induced kindling and pilocarpine-induced recurrent seizures. Although there is convincing evidence supporting that blood–brain-barrier (BBB) dysfunction facilitates seizures, no study has investigated whether the anticonvulsant effect of montelukast is associated with its ability to maintain BBB integrity. In this study we investigated whether montelukast and other CysLT receptor antagonists decrease PTZ-induced seizures, as well as whether these antagonists preserve BBB during PTZ-induced seizures. Adult male albino Swiss mice were stereotaxically implanted with a cannula into the right lateral ventricle, and two electrodes were placed over the parietal cortex along with a ground lead positioned over the nasal sinus for electroencephalography (EEG) recording. The effects of montelukast (0.03 or 0.3 μmol/1 μL, i.c.v.), pranlukast (1 or 3 μmol/1 μL, i.c.v.), Bay u-9773 (0.3, 3 or 30 nmol/1 μL, i.c.v.), in the presence or absence of the agonist LTD4 (0.2, 2, 6 or 20 pmol/1 μL, i.c.v.), on PTZ (1.8 μmol/2 μL)-induced seizures and BBB permeability disruption were determined. The animals were injected with the antagonists, agonist or vehicle 30 min before PTZ, and monitored for additional 30 min for the appearance of seizures by electrographic and behavioral methods. BBB permeability was assessed by sodium fluorescein method and by confocal microscopy for CD45 and IgG immunoreactivity. Bay-u9973 (3 and 30 nmol), montelukast (0.03 and 0.3 μmol) and pranlukast (1 and 3 μmol), increased the latency to generalized seizures and decreased the mean amplitude of EEG recordings during seizures. LTD4 (0.2 and 2 pmol) reverted the anticonvulsant effect of montelukast (0.3 μmol). Montelukast (0.03 and 0.3 μmol) prevented PTZ-induced BBB disruption, an effect that was reversed by LTD4 at the dose of 6 pmol, but not at the doses 0.2 and 2 pmol. Moreover, the doses of LTD4 (0.2 and 2 pmol) that reverted the effect of montelukast on seizures did not alter montelukast-induced protection of BBB, dissociating BBB protection and anticonvulsant activity. Confocal microscopy analysis revealed that 1. PTZ increased the number of CD45+ and double-immunofluorescence staining for CD45 and IgG cells in the cerebral cortex, indicating BBB leakage with leukocyte infiltration; 2. while LTD4 (6 pmol) potentiated, montelukast decreased the effect of PTZ on leukocyte migration and BBB, assessed by double-immunofluorescence staining for CD45 and IgG cells in the cannulated hemisphere. Our data do not allow us ruling out that mechanisms unrelated and related to BBB protection may co-exist, resulting in decreased seizure susceptibility by montelukast. Notwithstanding, they suggest that CysLT1 receptors may be a suitable target for anticonvulsant development.Fil: Lenz, Q.F.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Temp, F.R.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Poersch, A.B.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Masson, C.J.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Jesse, A.C.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Marafiga, J.R.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Reschke, C.R.. Universidade Federal de Santa Maria. Santa Maria; BrasilFil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Mello, C.F.. Universidade Federal de Santa Maria. Santa Maria; BrasilPergamon-Elsevier Science Ltd.2014-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/31960Mello, C.F.; Iribarren, Pablo; Reschke, C.R.; Marafiga, J.R.; Jesse, A.C.; Masson, C.J.; et al.; Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction; Pergamon-Elsevier Science Ltd.; Neuroscience; 277; 9-2014; 859-8710306-4522CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuroscience.2014.07.058info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0306452214006319info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:45:37Zoai:ri.conicet.gov.ar:11336/31960instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:45:37.874CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
title Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
spellingShingle Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
Lenz, Q.F.
Leukotrienes
Pentylenetetrazol
Seizure
Cyslt1r
Montelukast
title_short Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
title_full Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
title_fullStr Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
title_full_unstemmed Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
title_sort Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction
dc.creator.none.fl_str_mv Lenz, Q.F.
Arroyo, Daniela Soledad
Temp, F.R.
Poersch, A.B.
Masson, C.J.
Jesse, A.C.
Marafiga, J.R.
Reschke, C.R.
Iribarren, Pablo
Mello, C.F.
author Lenz, Q.F.
author_facet Lenz, Q.F.
Arroyo, Daniela Soledad
Temp, F.R.
Poersch, A.B.
Masson, C.J.
Jesse, A.C.
Marafiga, J.R.
Reschke, C.R.
Iribarren, Pablo
Mello, C.F.
author_role author
author2 Arroyo, Daniela Soledad
Temp, F.R.
Poersch, A.B.
Masson, C.J.
Jesse, A.C.
Marafiga, J.R.
Reschke, C.R.
Iribarren, Pablo
Mello, C.F.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leukotrienes
Pentylenetetrazol
Seizure
Cyslt1r
Montelukast
topic Leukotrienes
Pentylenetetrazol
Seizure
Cyslt1r
Montelukast
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Current evidence suggests that inflammation plays a role in the pathophysiology of seizures. In line with this view, selected pro-inflammatory arachidonic acid derivatives have been reported to facilitate seizures. Kainate-induced seizures are accompanied by leukotriene formation, and are reduced by inhibitors of LOX/COX pathway. Moreover, LTD4 receptor blockade and LTD4 synthesis inhibition suppress pentylenetetrazol (PTZ)-induced kindling and pilocarpine-induced recurrent seizures. Although there is convincing evidence supporting that blood–brain-barrier (BBB) dysfunction facilitates seizures, no study has investigated whether the anticonvulsant effect of montelukast is associated with its ability to maintain BBB integrity. In this study we investigated whether montelukast and other CysLT receptor antagonists decrease PTZ-induced seizures, as well as whether these antagonists preserve BBB during PTZ-induced seizures. Adult male albino Swiss mice were stereotaxically implanted with a cannula into the right lateral ventricle, and two electrodes were placed over the parietal cortex along with a ground lead positioned over the nasal sinus for electroencephalography (EEG) recording. The effects of montelukast (0.03 or 0.3 μmol/1 μL, i.c.v.), pranlukast (1 or 3 μmol/1 μL, i.c.v.), Bay u-9773 (0.3, 3 or 30 nmol/1 μL, i.c.v.), in the presence or absence of the agonist LTD4 (0.2, 2, 6 or 20 pmol/1 μL, i.c.v.), on PTZ (1.8 μmol/2 μL)-induced seizures and BBB permeability disruption were determined. The animals were injected with the antagonists, agonist or vehicle 30 min before PTZ, and monitored for additional 30 min for the appearance of seizures by electrographic and behavioral methods. BBB permeability was assessed by sodium fluorescein method and by confocal microscopy for CD45 and IgG immunoreactivity. Bay-u9973 (3 and 30 nmol), montelukast (0.03 and 0.3 μmol) and pranlukast (1 and 3 μmol), increased the latency to generalized seizures and decreased the mean amplitude of EEG recordings during seizures. LTD4 (0.2 and 2 pmol) reverted the anticonvulsant effect of montelukast (0.3 μmol). Montelukast (0.03 and 0.3 μmol) prevented PTZ-induced BBB disruption, an effect that was reversed by LTD4 at the dose of 6 pmol, but not at the doses 0.2 and 2 pmol. Moreover, the doses of LTD4 (0.2 and 2 pmol) that reverted the effect of montelukast on seizures did not alter montelukast-induced protection of BBB, dissociating BBB protection and anticonvulsant activity. Confocal microscopy analysis revealed that 1. PTZ increased the number of CD45+ and double-immunofluorescence staining for CD45 and IgG cells in the cerebral cortex, indicating BBB leakage with leukocyte infiltration; 2. while LTD4 (6 pmol) potentiated, montelukast decreased the effect of PTZ on leukocyte migration and BBB, assessed by double-immunofluorescence staining for CD45 and IgG cells in the cannulated hemisphere. Our data do not allow us ruling out that mechanisms unrelated and related to BBB protection may co-exist, resulting in decreased seizure susceptibility by montelukast. Notwithstanding, they suggest that CysLT1 receptors may be a suitable target for anticonvulsant development.
Fil: Lenz, Q.F.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Temp, F.R.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Poersch, A.B.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Masson, C.J.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Jesse, A.C.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Marafiga, J.R.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Reschke, C.R.. Universidade Federal de Santa Maria. Santa Maria; Brasil
Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Mello, C.F.. Universidade Federal de Santa Maria. Santa Maria; Brasil
description Current evidence suggests that inflammation plays a role in the pathophysiology of seizures. In line with this view, selected pro-inflammatory arachidonic acid derivatives have been reported to facilitate seizures. Kainate-induced seizures are accompanied by leukotriene formation, and are reduced by inhibitors of LOX/COX pathway. Moreover, LTD4 receptor blockade and LTD4 synthesis inhibition suppress pentylenetetrazol (PTZ)-induced kindling and pilocarpine-induced recurrent seizures. Although there is convincing evidence supporting that blood–brain-barrier (BBB) dysfunction facilitates seizures, no study has investigated whether the anticonvulsant effect of montelukast is associated with its ability to maintain BBB integrity. In this study we investigated whether montelukast and other CysLT receptor antagonists decrease PTZ-induced seizures, as well as whether these antagonists preserve BBB during PTZ-induced seizures. Adult male albino Swiss mice were stereotaxically implanted with a cannula into the right lateral ventricle, and two electrodes were placed over the parietal cortex along with a ground lead positioned over the nasal sinus for electroencephalography (EEG) recording. The effects of montelukast (0.03 or 0.3 μmol/1 μL, i.c.v.), pranlukast (1 or 3 μmol/1 μL, i.c.v.), Bay u-9773 (0.3, 3 or 30 nmol/1 μL, i.c.v.), in the presence or absence of the agonist LTD4 (0.2, 2, 6 or 20 pmol/1 μL, i.c.v.), on PTZ (1.8 μmol/2 μL)-induced seizures and BBB permeability disruption were determined. The animals were injected with the antagonists, agonist or vehicle 30 min before PTZ, and monitored for additional 30 min for the appearance of seizures by electrographic and behavioral methods. BBB permeability was assessed by sodium fluorescein method and by confocal microscopy for CD45 and IgG immunoreactivity. Bay-u9973 (3 and 30 nmol), montelukast (0.03 and 0.3 μmol) and pranlukast (1 and 3 μmol), increased the latency to generalized seizures and decreased the mean amplitude of EEG recordings during seizures. LTD4 (0.2 and 2 pmol) reverted the anticonvulsant effect of montelukast (0.3 μmol). Montelukast (0.03 and 0.3 μmol) prevented PTZ-induced BBB disruption, an effect that was reversed by LTD4 at the dose of 6 pmol, but not at the doses 0.2 and 2 pmol. Moreover, the doses of LTD4 (0.2 and 2 pmol) that reverted the effect of montelukast on seizures did not alter montelukast-induced protection of BBB, dissociating BBB protection and anticonvulsant activity. Confocal microscopy analysis revealed that 1. PTZ increased the number of CD45+ and double-immunofluorescence staining for CD45 and IgG cells in the cerebral cortex, indicating BBB leakage with leukocyte infiltration; 2. while LTD4 (6 pmol) potentiated, montelukast decreased the effect of PTZ on leukocyte migration and BBB, assessed by double-immunofluorescence staining for CD45 and IgG cells in the cannulated hemisphere. Our data do not allow us ruling out that mechanisms unrelated and related to BBB protection may co-exist, resulting in decreased seizure susceptibility by montelukast. Notwithstanding, they suggest that CysLT1 receptors may be a suitable target for anticonvulsant development.
publishDate 2014
dc.date.none.fl_str_mv 2014-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/31960
Mello, C.F.; Iribarren, Pablo; Reschke, C.R.; Marafiga, J.R.; Jesse, A.C.; Masson, C.J.; et al.; Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction; Pergamon-Elsevier Science Ltd.; Neuroscience; 277; 9-2014; 859-871
0306-4522
CONICET Digital
CONICET
url http://hdl.handle.net/11336/31960
identifier_str_mv Mello, C.F.; Iribarren, Pablo; Reschke, C.R.; Marafiga, J.R.; Jesse, A.C.; Masson, C.J.; et al.; Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood–brain barrier dysfunction; Pergamon-Elsevier Science Ltd.; Neuroscience; 277; 9-2014; 859-871
0306-4522
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuroscience.2014.07.058
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eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd.
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd.
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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