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 : 000314 ( PubMed/Checkpoint ); précédent : 000313; suivant : 000315Neuroprotective 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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<sourceDesc><biblStruct><analytic><title xml:lang="en">Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease.</title>
<author><name sortKey="Le Douaron, Gael" sort="Le Douaron, Gael" uniqKey="Le Douaron G" first="Gael" last="Le Douaron">Gael Le Douaron</name>
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<series><title level="j">European journal of medicinal chemistry</title>
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<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>
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<Month>12</Month>
<Day>08</Day>
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<DateCompleted><Year>2015</Year>
<Month>07</Month>
<Day>24</Day>
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<Day>07</Day>
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<Title>European journal of medicinal chemistry</Title>
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<ArticleTitle>Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease.</ArticleTitle>
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<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</CopyrightInformation>
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<ForeName>Gael</ForeName>
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