Cognitive impairments induced by concussive mild traumatic brain injury in mouse are ameliorated by treatment with phenserine via multiple non-cholinergic and cholinergic mechanisms

David Tweedie, Koji Fukui, Yazhou Li, Qian Sheng Yu, Shani Barak, Ian A. Tamargo, Vardit Rubovitch, Harold W. Holloway, Elin Lehrmann, William H. Wood, Yongqing Zhang, Kevin G. Becker, Evelyn Perez, Henriette Van Praag, Yu Luo, Barry J. Hoffer, Robert E. Becker, Chaim G. Pick, Nigel H. Greig

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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.

LanguageEnglish
Article numbere0156493
JournalPLoS One
Volume11
Issue number6
DOIs
StatePublished - 2016 Jun 1

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cholinergic agents
Cholinergic Agents
Brain
brain
Oxidative stress
oxidative stress
cholinesterase
mice
Cholinesterase Inhibitors
neuroprotective effect
neurodegenerative diseases
Alzheimer disease
thiobarbituric acid-reactive substances
glutathione peroxidase
glutamates
superoxide dismutase
lipid peroxidation
Thiobarbituric Acid Reactive Substances
animal models
Microarrays

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cognitive impairments induced by concussive mild traumatic brain injury in mouse are ameliorated by treatment with phenserine via multiple non-cholinergic and cholinergic mechanisms. / Tweedie, David; Fukui, Koji; Li, Yazhou; Yu, Qian Sheng; Barak, Shani; Tamargo, Ian A.; Rubovitch, Vardit; Holloway, Harold W.; Lehrmann, Elin; Wood, William H.; Zhang, Yongqing; Becker, Kevin G.; Perez, Evelyn; Van Praag, Henriette; Luo, Yu; Hoffer, Barry J.; Becker, Robert E.; Pick, Chaim G.; Greig, Nigel H.

In: PLoS One, Vol. 11, No. 6, e0156493, 01.06.2016.

Research output: Contribution to journalArticle

Tweedie, D, Fukui, K, Li, Y, Yu, QS, Barak, S, Tamargo, IA, Rubovitch, V, Holloway, HW, Lehrmann, E, Wood, WH, Zhang, Y, Becker, KG, Perez, E, Van Praag, H, Luo, Y, Hoffer, BJ, Becker, RE, Pick, CG & Greig, NH 2016, 'Cognitive impairments induced by concussive mild traumatic brain injury in mouse are ameliorated by treatment with phenserine via multiple non-cholinergic and cholinergic mechanisms' PLoS One, vol. 11, no. 6, e0156493. DOI: 10.1371/journal.pone.0156493
Tweedie, David ; Fukui, Koji ; Li, Yazhou ; Yu, Qian Sheng ; Barak, Shani ; Tamargo, Ian A. ; Rubovitch, Vardit ; Holloway, Harold W. ; Lehrmann, Elin ; Wood, William H. ; Zhang, Yongqing ; Becker, Kevin G. ; Perez, Evelyn ; Van Praag, Henriette ; Luo, Yu ; Hoffer, Barry J. ; Becker, Robert E. ; Pick, Chaim G. ; Greig, Nigel H./ Cognitive impairments induced by concussive mild traumatic brain injury in mouse are ameliorated by treatment with phenserine via multiple non-cholinergic and cholinergic mechanisms. In: PLoS One. 2016 ; Vol. 11, No. 6.
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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.",
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