title: Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms.
abstract: Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the 'Blalock Alzheimer's Disease Up' pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound's ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI.
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.|Division of Bioscience and Engineering, Shibaura Institute of Technology, Saitama 3378570, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukui
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Barak
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Tamargo
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.
authors.forename: Vardit
authors.initials: V
authors.lastname: Rubovitch
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.affiliation: Laboratory of Genetics and Genomics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.affiliation: Laboratory of Genetics and Genomics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.affiliation: Laboratory of Genetics and Genomics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Genetics and Genomics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Perez
authors.affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Henriette
authors.initials: H
authors.lastname: Van Praag
authors.affiliation: Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.|Independent Researcher, 7123 Pinebrook Road, Park City, UT 94098, United States of America.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Becker
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, 69978 Israel.
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, United States of America.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D018678:Cholinergic Agents / Q000008:administration & dosage; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010830:Physostigmine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D018698:Glutamic Acid; D010830:Physostigmine; C092280:phenserine