Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease.
Identifieur interne : 000564 ( Main/Exploration ); précédent : 000563; suivant : 000565Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease.
Auteurs : Gael Le Douaron [France] ; Fanny Schmidt [France] ; Majid Amar [France] ; Hanane Kadar [France] ; Lucila Debortoli [Brésil] ; Alexandra Latini [Brésil] ; Blandine Séon-Méniel [France] ; Laurent Ferrié [France] ; Patrick Pierre Michel [France] ; David Touboul [France] ; Alain Brunelle [France] ; Rita Raisman-Vozari [France] ; Bruno Figadère [France]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2015.
English descriptors
- KwdEn :
- Animals, Brain (drug effects), Brain (pathology), Cell Culture Techniques, Cells, Cultured, Dopaminergic Neurons (drug effects), Dopaminergic Neurons (pathology), Male, Mice, Inbred C57BL, Molecular Structure, Neuroprotective Agents (chemical synthesis), Neuroprotective Agents (chemistry), Neuroprotective Agents (pharmacokinetics), Neuroprotective Agents (pharmacology), Parkinson Disease (pathology), Quantitative Structure-Activity Relationship, Quinoxalines (chemical synthesis), Quinoxalines (chemistry), Quinoxalines (pharmacokinetics), Quinoxalines (pharmacology), Rats, Sprague-Dawley, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Distribution.
- MESH :
- chemical , chemical synthesis : Neuroprotective Agents, Quinoxalines.
- chemical , chemistry : Neuroprotective Agents, Quinoxalines.
- drug effects : Brain, Dopaminergic Neurons.
- pathology : Brain, Dopaminergic Neurons, Parkinson Disease.
- chemical , pharmacokinetics : Neuroprotective Agents, Quinoxalines.
- chemical , pharmacology : Neuroprotective Agents, Quinoxalines.
- Animals, Cell Culture Techniques, Cells, Cultured, Male, Mice, Inbred C57BL, Molecular Structure, Quantitative Structure-Activity Relationship, Rats, Sprague-Dawley, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Distribution.
Abstract
Parkinson disease is a neurodegenerative disorder of aging, characterized by disabling motor symptoms resulting from the loss of midbrain dopaminergic neurons and the decrease of dopamine in the striatum. Current therapies are directed at treating the symptoms but there is presently no cure for the disease. In order to discover neuroprotective compounds with a therapeutical potential, our research team has established original and highly regioselective methods for the synthesis of 2,3-disubstituted 6-aminoquinoxalines. To evaluate the neuroprotective activity of these molecules, we used midbrain cultures and various experimental conditions that promote dopaminergic cell loss. Among a series of 11 molecules, only compound MPAQ (2-methyl-3-phenyl-6-aminoquinoxaline) afforded substantial protection in a paradigm where dopaminergic neurons die spontaneously and progressively as they mature. Prediction of blood-brain barrier permeation by Quantitative Structure-Activity Relationship studies (QSARs) suggested that MPAQ was able to reach the brain parenchyma with sufficient efficacy. HPLC-MS/MS quantification in brain homogenates and MALDI-TOF mass spectrometry imaging on brain tissue sections performed in MPAQ-treated mice allowed us to confirm this prediction and to demonstrate, by MALDI-TOF mass spectrometry imaging, that MPAQ was localized in areas containing vulnerable neurons and/or their terminals. Of interest, MPAQ also rescued dopaminergic neurons, which (i) acquired dependency on the trophic peptide GDNF for their survival or (ii) underwent oxidative stress-mediated insults mediated by catalytically active iron. In summary, MPAQ possesses an interesting pharmacological profile as it penetrates the brain parenchyma and counteracts mechanisms possibly contributive to dopaminergic cell death in Parkinson disease.
DOI: 10.1016/j.ejmech.2014.10.067
PubMed: 25462259
Affiliations:
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Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Kadar, Hanane" sort="Kadar, Hanane" uniqKey="Kadar H" first="Hanane" last="Kadar">Hanane Kadar</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex</wicri:regionArea><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Debortoli, Lucila" sort="Debortoli, Lucila" uniqKey="Debortoli L" first="Lucila" last="Debortoli">Lucila Debortoli</name><affiliation wicri:level="1"><nlm:affiliation>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis</wicri:regionArea><wicri:noRegion>Trindade Florianópolis</wicri:noRegion></affiliation></author><author><name sortKey="Latini, Alexandra" sort="Latini, Alexandra" uniqKey="Latini A" first="Alexandra" last="Latini">Alexandra Latini</name><affiliation wicri:level="1"><nlm:affiliation>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis</wicri:regionArea><wicri:noRegion>Trindade Florianópolis</wicri:noRegion></affiliation></author><author><name sortKey="Seon Meniel, Blandine" sort="Seon Meniel, Blandine" uniqKey="Seon Meniel B" first="Blandine" last="Séon-Méniel">Blandine Séon-Méniel</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry</wicri:regionArea><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Ferrie, Laurent" sort="Ferrie, Laurent" uniqKey="Ferrie L" first="Laurent" last="Ferrié">Laurent Ferrié</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry</wicri:regionArea><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Michel, Patrick Pierre" sort="Michel, Patrick Pierre" uniqKey="Michel P" first="Patrick Pierre" last="Michel">Patrick Pierre Michel</name><affiliation wicri:level="3"><nlm:affiliation>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country 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uniqKey="Brunelle A" first="Alain" last="Brunelle">Alain Brunelle</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex</wicri:regionArea><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><affiliation wicri:level="3"><nlm:affiliation>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Figadere, Bruno" sort="Figadere, Bruno" uniqKey="Figadere B" first="Bruno" last="Figadère">Bruno Figadère</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France. 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wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Schmidt, Fanny" sort="Schmidt, Fanny" uniqKey="Schmidt F" first="Fanny" last="Schmidt">Fanny Schmidt</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Amar, Majid" sort="Amar, Majid" uniqKey="Amar M" first="Majid" last="Amar">Majid Amar</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Kadar, Hanane" sort="Kadar, Hanane" uniqKey="Kadar H" first="Hanane" last="Kadar">Hanane Kadar</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex</wicri:regionArea><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Debortoli, Lucila" sort="Debortoli, Lucila" uniqKey="Debortoli L" first="Lucila" last="Debortoli">Lucila Debortoli</name><affiliation wicri:level="1"><nlm:affiliation>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis</wicri:regionArea><wicri:noRegion>Trindade Florianópolis</wicri:noRegion></affiliation></author><author><name sortKey="Latini, Alexandra" sort="Latini, Alexandra" uniqKey="Latini A" first="Alexandra" last="Latini">Alexandra Latini</name><affiliation wicri:level="1"><nlm:affiliation>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis</wicri:regionArea><wicri:noRegion>Trindade Florianópolis</wicri:noRegion></affiliation></author><author><name sortKey="Seon Meniel, Blandine" sort="Seon Meniel, Blandine" uniqKey="Seon Meniel B" first="Blandine" last="Séon-Méniel">Blandine Séon-Méniel</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry</wicri:regionArea><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Ferrie, Laurent" sort="Ferrie, Laurent" uniqKey="Ferrie L" first="Laurent" last="Ferrié">Laurent Ferrié</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry</wicri:regionArea><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Michel, Patrick Pierre" sort="Michel, Patrick Pierre" uniqKey="Michel P" first="Patrick Pierre" last="Michel">Patrick Pierre Michel</name><affiliation wicri:level="3"><nlm:affiliation>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Touboul, David" sort="Touboul, David" uniqKey="Touboul D" first="David" last="Touboul">David Touboul</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex</wicri:regionArea><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Brunelle, Alain" sort="Brunelle, Alain" uniqKey="Brunelle A" first="Alain" last="Brunelle">Alain Brunelle</name><affiliation wicri:level="1"><nlm:affiliation>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex</wicri:regionArea><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion><wicri:noRegion>Gif-sur-Yvette Cedex</wicri:noRegion></affiliation></author><author><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><affiliation wicri:level="3"><nlm:affiliation>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Figadere, Bruno" sort="Figadere, Bruno" uniqKey="Figadere B" first="Bruno" last="Figadère">Bruno Figadère</name><affiliation wicri:level="4"><nlm:affiliation>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France. Electronic address: bruno.figadere@u-psud.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Nationale de la Recherche Scientifique (CNRS), Unité mixte de recherche (UMR) 8076 BioCIS, LabEx LERMIT, Laboratoire de Pharmacognosie, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry</wicri:regionArea><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><orgName type="university">Université Paris-Sud</orgName><placeName><settlement type="city">Orsay</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Brain (drug effects)</term><term>Brain (pathology)</term><term>Cell Culture Techniques</term><term>Cells, Cultured</term><term>Dopaminergic Neurons (drug effects)</term><term>Dopaminergic Neurons (pathology)</term><term>Male</term><term>Mice, Inbred C57BL</term><term>Molecular Structure</term><term>Neuroprotective Agents (chemical synthesis)</term><term>Neuroprotective Agents (chemistry)</term><term>Neuroprotective Agents (pharmacokinetics)</term><term>Neuroprotective Agents (pharmacology)</term><term>Parkinson Disease (pathology)</term><term>Quantitative Structure-Activity Relationship</term><term>Quinoxalines (chemical synthesis)</term><term>Quinoxalines (chemistry)</term><term>Quinoxalines (pharmacokinetics)</term><term>Quinoxalines (pharmacology)</term><term>Rats, Sprague-Dawley</term><term>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</term><term>Tissue Distribution</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Neuroprotective Agents</term><term>Quinoxalines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Neuroprotective Agents</term><term>Quinoxalines</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brain</term><term>Dopaminergic Neurons</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Brain</term><term>Dopaminergic Neurons</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Neuroprotective Agents</term><term>Quinoxalines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Neuroprotective Agents</term><term>Quinoxalines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Culture Techniques</term><term>Cells, Cultured</term><term>Male</term><term>Mice, Inbred C57BL</term><term>Molecular Structure</term><term>Quantitative Structure-Activity Relationship</term><term>Rats, Sprague-Dawley</term><term>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</term><term>Tissue Distribution</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson disease is a neurodegenerative disorder of aging, characterized by disabling motor symptoms resulting from the loss of midbrain dopaminergic neurons and the decrease of dopamine in the striatum. Current therapies are directed at treating the symptoms but there is presently no cure for the disease. In order to discover neuroprotective compounds with a therapeutical potential, our research team has established original and highly regioselective methods for the synthesis of 2,3-disubstituted 6-aminoquinoxalines. To evaluate the neuroprotective activity of these molecules, we used midbrain cultures and various experimental conditions that promote dopaminergic cell loss. Among a series of 11 molecules, only compound MPAQ (2-methyl-3-phenyl-6-aminoquinoxaline) afforded substantial protection in a paradigm where dopaminergic neurons die spontaneously and progressively as they mature. Prediction of blood-brain barrier permeation by Quantitative Structure-Activity Relationship studies (QSARs) suggested that MPAQ was able to reach the brain parenchyma with sufficient efficacy. HPLC-MS/MS quantification in brain homogenates and MALDI-TOF mass spectrometry imaging on brain tissue sections performed in MPAQ-treated mice allowed us to confirm this prediction and to demonstrate, by MALDI-TOF mass spectrometry imaging, that MPAQ was localized in areas containing vulnerable neurons and/or their terminals. Of interest, MPAQ also rescued dopaminergic neurons, which (i) acquired dependency on the trophic peptide GDNF for their survival or (ii) underwent oxidative stress-mediated insults mediated by catalytically active iron. In summary, MPAQ possesses an interesting pharmacological profile as it penetrates the brain parenchyma and counteracts mechanisms possibly contributive to dopaminergic cell death in Parkinson disease.</div></front></TEI><affiliations><list><country><li>Brésil</li><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Orsay</li><li>Paris</li></settlement><orgName><li>Université Paris-Sud</li></orgName></list><tree><country name="France"><region name="Île-de-France"><name sortKey="Le Douaron, Gael" sort="Le Douaron, Gael" uniqKey="Le Douaron G" first="Gael" last="Le Douaron">Gael Le Douaron</name></region><name sortKey="Amar, Majid" sort="Amar, Majid" uniqKey="Amar M" first="Majid" last="Amar">Majid Amar</name><name sortKey="Brunelle, Alain" sort="Brunelle, Alain" uniqKey="Brunelle A" first="Alain" last="Brunelle">Alain Brunelle</name><name sortKey="Ferrie, Laurent" sort="Ferrie, Laurent" uniqKey="Ferrie L" first="Laurent" last="Ferrié">Laurent Ferrié</name><name sortKey="Figadere, Bruno" sort="Figadere, Bruno" uniqKey="Figadere B" first="Bruno" last="Figadère">Bruno Figadère</name><name sortKey="Kadar, Hanane" sort="Kadar, Hanane" uniqKey="Kadar H" first="Hanane" last="Kadar">Hanane Kadar</name><name sortKey="Michel, Patrick Pierre" sort="Michel, Patrick Pierre" uniqKey="Michel P" first="Patrick Pierre" last="Michel">Patrick Pierre Michel</name><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><name sortKey="Schmidt, Fanny" sort="Schmidt, Fanny" uniqKey="Schmidt F" first="Fanny" last="Schmidt">Fanny Schmidt</name><name sortKey="Seon Meniel, Blandine" sort="Seon Meniel, Blandine" uniqKey="Seon Meniel B" first="Blandine" last="Séon-Méniel">Blandine Séon-Méniel</name><name sortKey="Touboul, David" sort="Touboul, David" uniqKey="Touboul D" first="David" last="Touboul">David Touboul</name></country><country name="Brésil"><noRegion><name sortKey="Debortoli, Lucila" sort="Debortoli, Lucila" uniqKey="Debortoli L" first="Lucila" last="Debortoli">Lucila Debortoli</name></noRegion><name sortKey="Latini, Alexandra" sort="Latini, Alexandra" uniqKey="Latini A" first="Alexandra" last="Latini">Alexandra Latini</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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