title: Loss of quinone reductase 2 function selectively facilitates learning behaviors.
abstract: High levels of reactive oxygen species (ROS) are associated with deficits in learning and memory with age as well as in Alzheimer's disease. Using DNA microarray, we demonstrated the overexpression of quinone reductase 2 (QR2) in the hippocampus in two models of learning deficits, namely the aged memory impaired rats and the scopolamine-induced amnesia model. QR2 is a cytosolic flavoprotein that catalyzes the reduction of its substrate and enhances the production of damaging activated quinone and ROS. QR2-like immunostaining is enriched in cerebral structures associated with learning behaviors, such as the hippocampal formation and the temporofrontal cortex of rat, mouse, and human brains. In cultured rat embryonic hippocampal neurons, selective inhibitors of QR2, namely S26695 and S29434, protected against menadione-induced cell death by reversing its proapoptotic action. S26695 (8 mg/kg) also significantly inhibited scopolamine-induced amnesia. Interestingly, adult QR2 knock-out mice demonstrated enhanced learning abilities in various tasks, including Morris water maze, object recognition, and rotarod performance test. Other behaviors related to anxiety (elevated plus maze), depression (forced swim), and schizophrenia (prepulse inhibition) were not affected in QR2-deficient mice. Together, these data suggest a role for QR2 in cognitive behaviors with QR2 inhibitors possibly representing a novel therapeutic strategy toward the treatment of learning deficits especially observed in the aged brain.
authors.affiliation: Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Verdun, Québec, Canada.
authors.forename: Charles-Etienne
authors.initials: CE
authors.lastname: Benoit
authors.forename: Stephane
authors.initials: S
authors.lastname: Bastianetto
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brouillette
authors.forename: YiuChung
authors.initials: Y
authors.lastname: Tse
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: TakPan
authors.initials: T
authors.lastname: Wong
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.forename: Rémi
authors.initials: R
authors.lastname: Quirion
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D011808:Quinone Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045442:Rotarod Performance Test; D013550:Swimming
chemical_list: C550454:N-(2-(2-methoxy-6H-dipyrido(2,3-a-3,2-e)pyrrolizin-11-yl)ethyl)-2-furamide; D011725:Pyridines; D011763:Pyrrolizidine Alkaloids; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases