Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice
Organophosphate pesticides and nerve agents (OPs), are characterized by cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation l...
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Elsevier
2021-05-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121000255 |
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doaj-a2925ef027ff413ab4ff53a35214c3ee |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Clémence Maupu Julie Enderlin Alexandre Igert Myriam Oger Stéphane Auvin Rahma Hassan-Abdi Nadia Soussi-Yanicostas Xavier Brazzolotto Florian Nachon Grégory Dal Bo Nina Dupuis |
spellingShingle |
Clémence Maupu Julie Enderlin Alexandre Igert Myriam Oger Stéphane Auvin Rahma Hassan-Abdi Nadia Soussi-Yanicostas Xavier Brazzolotto Florian Nachon Grégory Dal Bo Nina Dupuis Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice Neurobiology of Disease Astrocyte Microglia Cytokines Seizure DFP Organophosphates |
author_facet |
Clémence Maupu Julie Enderlin Alexandre Igert Myriam Oger Stéphane Auvin Rahma Hassan-Abdi Nadia Soussi-Yanicostas Xavier Brazzolotto Florian Nachon Grégory Dal Bo Nina Dupuis |
author_sort |
Clémence Maupu |
title |
Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice |
title_short |
Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice |
title_full |
Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice |
title_fullStr |
Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice |
title_full_unstemmed |
Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice |
title_sort |
diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2021-05-01 |
description |
Organophosphate pesticides and nerve agents (OPs), are characterized by cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation leading to profound pathological alterations of the brain.The aim of this study was to characterize neuroinflammatory responses at key time points after SE induced by the OP, diisopropylfluorophosphate (DFP). Immunohistochemistry (IHC) analysis and RT-qPCR on cerebral tissue are often insufficient to identity and quantify precise neuroinflammatory alterations. To address these needs, we performed RT-qPCR quantification after whole brain magnetic-activated cell-sorting (MACS) of CD11B (microglia/infiltrated macrophages) and GLAST (astrocytes)-positive cells at 1, 4, 24 h and 3 days post-SE. In order to compare these results to those obtained by IHC, we performed, classical Iba1 (microglia/infiltrated macrophages) and GFAP (astrocytes) IHC analysis in parallel, focusing on the hippocampus, a brain region affected by seizure activity and neurodegeneration.Shortly after SE (1–4 h), an increase in pro-inflammatory (M1-like) markers and A2-specific markers, proposed as neurotrophic, were observed in CD11B and GLAST-positive isolated cells, respectively. Microglial cells successively expressed immuno-regulatory (M2b-like) and anti-inflammatory (M2a-like) at 4 h and 24 h post-SE induction. At 24 h and 3 days, A1-specific markers, proposed as neurotoxic, were increased in isolated astrocytes. Although IHC analysis presented no modification in terms of percentage of marked area and cell number at 1 and 4 h after SE, at 24 h and 3 days after SE, microglial and astrocytic activation was visible by IHC as an increase in Iba1 and GFAP-positive area and Iba1-positive cells in DFP animals when compared to the control.Our work identified sequential microglial and astrocytic phenotype activation. Although the role of each phenotype in SE cerebral outcomes requires further study, targeting specific markers at specific time point could be a beneficial strategy for DFP-induced SE treatment. |
topic |
Astrocyte Microglia Cytokines Seizure DFP Organophosphates |
url |
http://www.sciencedirect.com/science/article/pii/S0969996121000255 |
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doaj-a2925ef027ff413ab4ff53a35214c3ee2021-03-22T08:43:09ZengElsevierNeurobiology of Disease1095-953X2021-05-01152105276Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male miceClémence Maupu0Julie Enderlin1Alexandre Igert2Myriam Oger3Stéphane Auvin4Rahma Hassan-Abdi5Nadia Soussi-Yanicostas6Xavier Brazzolotto7Florian Nachon8Grégory Dal Bo9Nina Dupuis10Département de Toxicologie et risques chimiques, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, FranceUniversité de Paris, NeuroDiderot, Inserm, F-75019 Paris, France; Service de neurologie pédiatrique, AP-HP, Hôpital Robert Debré, F-75019 Paris, FranceDépartement de Toxicologie et risques chimiques, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, FranceUnité Imagerie, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, FranceUniversité de Paris, NeuroDiderot, Inserm, F-75019 Paris, France; Service de neurologie pédiatrique, AP-HP, Hôpital Robert Debré, F-75019 Paris, FranceUniversité de Paris, NeuroDiderot, Inserm, F-75019 Paris, FranceUniversité de Paris, NeuroDiderot, Inserm, F-75019 Paris, FranceDépartement de Toxicologie et risques chimiques, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, FranceDépartement de Toxicologie et risques chimiques, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, FranceDépartement de Toxicologie et risques chimiques, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, FranceDépartement de Toxicologie et risques chimiques, Institut de recherche biomédicale des armées, BP73, F-91223 Brétigny sur Orge cedex, France; Corresponding author at: Institut de recherche biomédicale des armées, 1 Place Général Valérie André, BP 73, 91223 Brétigny sur Orge cedex, France.Organophosphate pesticides and nerve agents (OPs), are characterized by cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation leading to profound pathological alterations of the brain.The aim of this study was to characterize neuroinflammatory responses at key time points after SE induced by the OP, diisopropylfluorophosphate (DFP). Immunohistochemistry (IHC) analysis and RT-qPCR on cerebral tissue are often insufficient to identity and quantify precise neuroinflammatory alterations. To address these needs, we performed RT-qPCR quantification after whole brain magnetic-activated cell-sorting (MACS) of CD11B (microglia/infiltrated macrophages) and GLAST (astrocytes)-positive cells at 1, 4, 24 h and 3 days post-SE. In order to compare these results to those obtained by IHC, we performed, classical Iba1 (microglia/infiltrated macrophages) and GFAP (astrocytes) IHC analysis in parallel, focusing on the hippocampus, a brain region affected by seizure activity and neurodegeneration.Shortly after SE (1–4 h), an increase in pro-inflammatory (M1-like) markers and A2-specific markers, proposed as neurotrophic, were observed in CD11B and GLAST-positive isolated cells, respectively. Microglial cells successively expressed immuno-regulatory (M2b-like) and anti-inflammatory (M2a-like) at 4 h and 24 h post-SE induction. At 24 h and 3 days, A1-specific markers, proposed as neurotoxic, were increased in isolated astrocytes. Although IHC analysis presented no modification in terms of percentage of marked area and cell number at 1 and 4 h after SE, at 24 h and 3 days after SE, microglial and astrocytic activation was visible by IHC as an increase in Iba1 and GFAP-positive area and Iba1-positive cells in DFP animals when compared to the control.Our work identified sequential microglial and astrocytic phenotype activation. Although the role of each phenotype in SE cerebral outcomes requires further study, targeting specific markers at specific time point could be a beneficial strategy for DFP-induced SE treatment.http://www.sciencedirect.com/science/article/pii/S0969996121000255AstrocyteMicrogliaCytokinesSeizureDFPOrganophosphates |