title: Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice.
abstract: Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin's effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation.
authors.affiliation: Dept of Physiology and Biophysics, Howard University College of Medicine, 520 W St. NW, Washington DC 20059, USA; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA. Electronic address: joanne.allard@howard.edu.
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Allard
authors.affiliation: Neurocognitive Aging Section, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Evelyn J
authors.initials: EJ
authors.lastname: Perez
authors.affiliation: Physiological Chemistry Laboratory, Department of Bioscience and Engineering, Shibaura Institute of Technology, Fukasaku 307, Minuma-ku, Saitama 3378570, Japan; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukui
authors.affiliation: Dept of Physiology and Biophysics, Howard University College of Medicine, 520 W St. NW, Washington DC 20059, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Carpenter
authors.affiliation: Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State university System, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: Donald K
authors.initials: DK
authors.lastname: Ingram
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA. Electronic address: decabora@grc.nia.nih.gov.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects; D000375:Aging / Q000187:drug effects* / Q000502:physiology / Q000523:psychology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008687:Metformin / Q000009:adverse effects*; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation
chemical_list: D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D051267:NF-E2-Related Factor 2; D020933:Neurotrophin 3; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: BDNF; Metformin; NGF; Neurotrophin 3; Nrf2; Water maze