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10.1371/journal.pone.0156493 http://scihub22266oqcxt.onion/10.1371/journal.pone.0156493 C4890804!4890804 !27254111     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27254111 &cmd=llinks): Failed to open stream: HTTP request failed! 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Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms |pdf=|usr=}}{{27254111 }} gab.com Text Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms JO: PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=27254111 #FOAvip 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. Twit Text FOAVip 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 http://www.kidney.de/pget.php?&tw=1&pmid=27254111 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27254111 #FOAvip English Wikipedia <ref>{{Cite pmid|27254111 }}</ref> Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms #MMPMID27254111 Tweedie D ; Fukui K ; Li Y ; Yu QS ; Barak S ; Tamargo IA ; Rubovitch V ; Holloway HW ; Lehrmann E ; Wood WH 3rd ; Zhang Y ; Becker KG ; Perez E ; Van Praag H ; Luo Y ; Hoffer BJ ; Becker RE ; Pick CG ; Greig NH PLoS One 2016[]; 11 (6 ): e0156493 PMID27254111 show ga 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. |Animals [MESH] |Brain Concussion/complications/*drug therapy/pathology [MESH] |Cholinergic Agents/administration & dosage [MESH] |Cholinesterase Inhibitors/administration & dosage [MESH] |Cognitive Dysfunction/*drug therapy/etiology/pathology [MESH] |Disease Models, Animal [MESH] |Gene Expression Regulation/drug effects [MESH] |Glutamic Acid/metabolism [MESH] |Hippocampus/drug effects/metabolism [MESH] |Humans [MESH] |Lipid Peroxidation/drug effects [MESH] |Maze Learning/drug effects [MESH] |Mice [MESH] |Neurons/drug effects/pathology [MESH] |Oxidative Stress/*drug effects [MESH]Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injur(epmc).pdf DeepDyve Pubget Overpricing