title: Mechanical ventilation triggers hippocampal apoptosis by vagal and dopaminergic pathways.
abstract: BACKGROUND
  Critically ill patients frequently develop neuropsychological disturbances including acute delirium or memory impairment. The need for mechanical ventilation is a risk factor for these adverse events, but a mechanism that links lung stretch and brain injury has not been identified.
  
  
  OBJECTIVE
  To identify the mechanisms that lead to brain dysfunction during mechanical ventilation.
  
  
  METHODS
  Brains from mechanically ventilated mice were harvested, and signals of apoptosis and alterations in the Akt survival pathway were studied. These measurements were repeated in vagotomized or haloperidol-treated mice, and in animals intracerebroventricularly injected with selective dopamine-receptor blockers. Hippocampal slices were cultured and treated with micromolar concentrations of dopamine, with or without dopamine receptor blockers. Last, levels of dysbindin, a regulator of the membrane availability of dopamine receptors, were assessed in the experimental model and in brain samples from ventilated patients.
  
  
  RESULTS
  Mechanical ventilation triggers hippocampal apoptosis as a result of type 2 dopamine receptor activation in response to vagal signaling. Activation of these receptors blocks the Akt/GSK3β prosurvival pathway and activates the apoptotic cascade, as demonstrated in vivo and in vitro. Vagotomy, systemic haloperidol, or intracerebroventricular raclopride (a type 2 dopamine receptor blocker) ameliorated this effect. Moreover, ventilation induced a concomitant change in the expression of dysbindin-1C. These results were confirmed in brain samples from ventilated patients.
  
  
  CONCLUSIONS
  These results prove the existence of a pathogenic mechanism of lung stretch-induced hippocampal apoptosis that could explain the neurological changes in ventilated patients and may help to identify novel therapeutic approaches.
authors: 1 Departamento de Biología Funcional, Área de Fisiología, Instituto Universitario de Oncología del Principado de Asturias, and.
authors: Adrián
authors: A
authors: González-López
authors: Inés
authors: I
authors: López-Alonso
authors: Alina
authors: A
authors: Aguirre
authors: Laura
authors: L
authors: Amado-Rodríguez
authors: Estefanía
authors: E
authors: Batalla-Solís
authors: Aurora
authors: A
authors: Astudillo
authors: Cristina
authors: C
authors: Tomás-Zapico
authors: Antonio
authors: A
authors: Fueyo
authors: Claudia C
authors: CC
authors: dos Santos
authors: Konrad
authors: K
authors: Talbot
authors: Guillermo M
authors: GM
authors: Albaiceta
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D012121:Respiration, Artificial / Q000009:adverse effects*; D015398:Signal Transduction; D014630:Vagus Nerve / Q000378:metabolism / Q000473:pathology*; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C432416:DTNBP1 protein, human; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004298:Dopamine