Mechanical ventilation triggers hippocampal apoptosis by vagal and dopaminergic pathways

Am J Respir Crit Care Med. 2013 Sep 15;188(6):693-702. doi: 10.1164/rccm.201304-0691OC.

Abstract

Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Carrier Proteins / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Respiration, Artificial / adverse effects*
  • Signal Transduction
  • Vagus Nerve / metabolism
  • Vagus Nerve / pathology*
  • Ventilator-Induced Lung Injury / metabolism*

Substances

  • Carrier Proteins
  • DTNBP1 protein, human
  • Dtnbp1 protein, mouse
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Dopamine