title: Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury.
abstract: Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2α]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology. Exposure of cells to guanabenz has been shown to increase eIF2α phosphorylation and reduce ER stress. Using a rodent model of TBI, we present experimental results that indicate that postinjury administration of 5.0 mg/kg of guanabenz reduced cortical contusion volume and decreased hippocampal cell damage. Moreover, guanabenz treatment attenuated TBI-associated motor, vestibulomotor, recognition memory, and spatial learning and memory dysfunction. Interestingly, when the initiation of treatment was delayed by 24 h, or the dose reduced to 0.5 mg/kg, some of these beneficial effects were still observed. Taken together, these findings further support the involvement of ER stress signaling in TBI pathophysiology and indicate that guanabenz may have translational utility.
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
authors.affiliation: 2 Department of Psychology, Southern Illinois University , Carbondale, Illinois.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hylin
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Hood
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Orsi
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: John B
authors.initials: JB
authors.lastname: Redell
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Tsvetkov
authors.affiliation: 1 Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston , Houston, Texas.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Moore
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D006143:Guanabenz / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D065853:Spatial Learning / Q000187:drug effects*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; C019363:eIF-2 phosphatase; D010749:Phosphoprotein Phosphatases; D006143:Guanabenz
keywords: CHOP; ER stress; TBI; hippocampus; phosphatase
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