title: The neuroprotective effect of salubrinal in a mouse model of traumatic brain injury.
abstract: We have previously reported that mild traumatic brain injury (mTBI) induced cognitive deficits as well as apoptotic changes in the brains of mice. Apoptosis may be caused by severe, prolonged accumulation of misfolded proteins, and protein aggregation in the endoplasmic reticulum (ER stress). In an additional study, we have reported that mTBI activated the pro-apoptotic arm of the integrated stress response (ISR). The main goal of the present study was to test the involvement of the adaptive eIF2α/ATF4 pathway in mTBI-affected brains. Head injury was induced with a noninvasive, closed-head weight drop (30 g) to ICR mice. Salubrinal, the selective phosphatase inhibitor of p-eIF2α, was injected immediately and 24 h after mTBI (1 mg/kg, ip). Y-maze and novel object recognition tests to assess spatial and visual memories, respectively, were conducted either 7 or 30 days post-trauma. Salubrinal administration significantly improved memory deficits following mTBI. Slaubrinal also prevented the elevation of degenerating neurons and the reduction of mature neurons in the cortex (as seen by immunofluorescent staining with Fluoro-Jade-B and NeuN antibodies, 72 h and 1 week post-mTBI, respectively). Western blot analysis revealed that salubrinal prevented the significant reduction in eIF2α and ATF4 phosphorylation in mTBI brains 72 h post-injury. Immunofluorescence staining revealed that although the reduction in p-eIF2α did not reach significance, salubrinal administration elevated it dramatically. Our results show that targeting the translational/adaptive arm of the ISR with salubrinal may serve as a therapeutic strategy for brain damage.
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel, rubovitc@post.tau.ac.il.
authors.forename: Vardit
authors.initials: V
authors.lastname: Rubovitch
authors.forename: Shani
authors.initials: S
authors.lastname: Barak
authors.forename: Lital
authors.initials: L
authors.lastname: Rachmany
authors.forename: Renana Baratz
authors.initials: RB
authors.lastname: Goldstein
authors.forename: Yael
authors.initials: Y
authors.lastname: Zilberstein
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
mesh_terms: D051701:Activating Transcription Factor 4 / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D002540:Cerebral Cortex / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D002934:Cinnamates / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000502:physiology; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014949:Wounds, Nonpenetrating / Q000150:complications / Q000188:drug therapy
chemical_list: C081452:Atf4 protein, mouse; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C496827:salubrinal; D051701:Activating Transcription Factor 4; D013890:Thiourea