title: Nrf2-Mediated Neuroprotection Against Recurrent Hypoglycemia Is Insufficient to Prevent Cognitive Impairment in a Rodent Model of Type 1 Diabetes.
abstract: It remains uncertain whether recurrent nonsevere hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2(-/-) ± T1D and ± Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control, mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1 In Nrf2(-/-) mice, both T1D and Hypo independently resulted in impaired cognitive performance, and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D, this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
authors.forename: Alison D
authors.initials: AD
authors.lastname: McNeilly
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gallagher
authors.affiliation: Division of Cancer Research, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: Division of Cancer Research, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K. Division of Neuroscience, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Sharkey
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K.
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, U.K. r.mccrimmon@dundee.ac.uk.
authors.forename: Rory J
authors.initials: RJ
authors.lastname: McCrimmon
mesh_terms: D000818:Animals; D060825:Cognitive Dysfunction / Q000378:metabolism / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism* / Q000503:physiopathology*; D007249:Inflammation / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D016133:Polymerase Chain Reaction; D011897:Random Allocation
chemical_list: D051267:NF-E2-Related Factor 2