title: Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury.
abstract: The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway mediates many aspects of cell growth and regeneration and is upregulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signaling event for recovery of brain function is presently unclear. We analyzed the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI) and identified an early neuronal peak of activity that occurs within a few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin 1 h after CCI and showed that this acute treatment significantly diminishes the extent of neuronal death, astrogliosis, and cognitive impairment 1-3 days after injury. Our findings suggest that the early neuronal peak of mTORC1 activity after TBI is deleterious to brain function, and that acute, early intervention with mTORC1 inhibitors after injury may represent an effective form of treatment to improve recovery in human patients.
authors.affiliation: 1 Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey , Piscataway, New Jersey.|2 Graduate Program in Molecular Bioscience, Rutgers, the State University of New Jersey , Piscataway, New Jersey.
authors.forename: Ina
authors.initials: I
authors.lastname: Nikolaeva
authors.affiliation: 1 Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey , Piscataway, New Jersey.
authors.forename: Beth
authors.initials: B
authors.lastname: Crowell
authors.affiliation: 3 Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Julia
authors.initials: J
authors.lastname: Valenziano
authors.affiliation: 3 Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Meaney
authors.affiliation: 1 Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey , Piscataway, New Jersey.|2 Graduate Program in Molecular Bioscience, Rutgers, the State University of New Jersey , Piscataway, New Jersey.
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Arcangelo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: controlled cortical impact; mTOR; rapamycin