Vagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury

J Trauma Acute Care Surg. 2012 Jun;72(6):1562-6. doi: 10.1097/TA.0b013e3182569875.


Background: Traumatic brain injury (TBI) may alter sympathetic tone causing autonomic abnormalities and organ dysfunction. Vagal nerve stimulation (VNS) has been shown to decrease inflammation and distant organ injury after TBI. It is unknown whether VNS may reduce blood-brain barrier (BBB) dysfunction after TBI.We hypothesize that VNS prevents TBI-induced breakdown of the BBB, subsequent brain edema, and neuronal injury.

Methods: A weight-drop model was used to create severe TBI in balb/c mice. Animals were divided into three groups: TBI-TBI only; TBI or VNS--animals that were treated with 10 minutes of VNS immediately before TBI; and sham--animals with opening of the skull but no TBI and VNS treatment. Brain vascular permeability to injected (Mr 70,000) FITC-dextran was measured by radiated fluorescence 6 hours after injury. Injured tissue sections were stained for perivascular aquaporin 4 (AQP-4), an important protein causing BBB--mediated brain edema. Fluorescence was quantified under laser scanning by confocal microscopy.

Results: Six hours after TBI, cerebral vascular permeability was increased fourfold compared with sham (mean [SD], 6.6(E+08) [5.5(E+07)] arbitrary fluorescence units [afu] vs. 1.5(E+08) [2.9(E+07)] afu; p G 0.001). VNS prevented the increase in permeability when compared with TBI alone (mean [SD], 3.5 (E+08) [8.3(E+07)] afu vs. 6.6(E+08) [5.5(E+07)] afu; p G 0.05). Perivascular expression of AQP-4 was increased twofold in TBI animals compared with sham (mean [SD], 0.96 [0.12] afu vs. 1.79 [0.37] afu; p G 0.05). Similarly, VNS decreased post-TBI expression of AQP-4 to levels similar to sham (mean [SD], 1.15 [0.12] afu; p G 0.05).

Conclusion: VNS attenuates cerebral vascular permeability and decreases the up-regulation of AQP-4 after TBI. Future studies are needed to assess the mechanisms by which VNS maintains the BBB.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism*
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / physiopathology*
  • Brain Injuries / metabolism
  • Brain Injuries / pathology*
  • Brain Injuries / therapy*
  • Dextrans / pharmacokinetics*
  • Disease Models, Animal
  • Fluorescein-5-isothiocyanate / analogs & derivatives*
  • Fluorescein-5-isothiocyanate / pharmacokinetics
  • Fluorescence
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Confocal
  • Random Allocation
  • Reference Values
  • Treatment Outcome
  • Up-Regulation
  • Vagus Nerve Stimulation / methods*


  • Aquaporin 4
  • Dextrans
  • fluorescein isothiocyanate dextran
  • Fluorescein-5-isothiocyanate