title: Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease.
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.
authors.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.
authors.forename: Gael
authors.initials: G
authors.lastname: Le Douaron
authors.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.
authors.forename: Fanny
authors.initials: F
authors.lastname: Schmidt
authors.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.
authors.forename: Majid
authors.initials: M
authors.lastname: Amar
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.
authors.forename: Hanane
authors.initials: H
authors.lastname: Kadar
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis, Brazil.
authors.forename: Lucila
authors.initials: L
authors.lastname: Debortoli
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade Florianópolis, Brazil.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
authors.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.
authors.forename: Blandine
authors.initials: B
authors.lastname: Séon-Méniel
authors.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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ferrié
authors.affiliation: Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Patrick Pierre
authors.initials: PP
authors.lastname: Michel
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.
authors.forename: David
authors.initials: D
authors.lastname: Touboul
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Brunelle
authors.affiliation: Sorbonne Université Pierre et Marie Curie-Paris UM75, INSERM U1127, CNRS UMR7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Figadère
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010300:Parkinson Disease / Q000473:pathology*; D021281:Quantitative Structure-Activity Relationship; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution
chemical_list: D018696:Neuroprotective Agents; D011810:Quinoxalines
keywords: Biological screening; MALDI-TOF imaging; Medicinal chemistry; Neurodegenerative disease; Parkinson disease; Quinoxaline