title: Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction.
abstract: OBJECTIVE
  Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional.
  
  
  METHODS
  A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin.
  
  
  RESULTS
  Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome c release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvement in hippocampal function: prohibitin expression ameliorated the spatial memory deficit induced by ischemia, assessed by the Y-maze test, and restored postischemic synaptic plasticity assessed by long-term potentiation, indicating that the neurons spared form ischemic damage were functionally competent.
  
  
  CONCLUSIONS
  These data demonstrate that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggest that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis. Measures to enhance prohibitin expression could have translational value in ischemic brain injury and, possibly, other forms of brain injury associated with mitochondrial dysfunction.
authors.affiliation: From the Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (H.K., M.S., L.Q., K.K., L.P., G.M., C.I., P.Z.); and Center for Neural Science, New York University, New York, NY (T.M., E.K.).
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kurinami
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Liping
authors.initials: L
authors.lastname: Qian
authors.forename: Kenzo
authors.initials: K
authors.lastname: Koizumi
authors.forename: Laibaik
authors.initials: L
authors.lastname: Park
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002452:Cell Count; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006323:Heart Arrest / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins
keywords: brain ischemia; mitochondria; prohibitin