title: Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory.
abstract: High fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10mg/kg/day BM orally for 21weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF diet-induced impairment in recognition memory (p<0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p<0.05), however, no changes were seen in the hippocampus (p>0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p<0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus.
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Camer
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; ANSTO LifeSciences, Australian Nuclear Science and Technology Organisation, NSW 2234, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Szabo
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; Faculty of Social Sciences, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2522, Australia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fernandez
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
authors.forename: Chi H L
authors.initials: CHL
authors.lastname: Dinh
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong and Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia. Electronic address: xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000818:Animals; D001345:Autoradiography; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D018709:Statistics, Nonparametric; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D018696:Neuroprotective Agents; D014316:Tritium; D016291:Dizocilpine Maleate; D009828:Oleanolic Acid; C445068:bardoxolone methyl
keywords: Bardoxolone methyl; Hippocampus; Obesity; Prefrontal cortex; Recognition memory