Sphenopalatine ganglion stimulation is a reversible and frequency-dependent modulator of the blood-brain barrier

Brain Res. 2019 Sep 1:1718:231-241. doi: 10.1016/j.brainres.2019.04.030. Epub 2019 Apr 26.


Background: The sphenopalatine ganglion (SPG) is a vasoactive mediator of the anterior intracranial circulation in mammals. SPG stimulation has been demonstrated to alter blood-brain barrier (BBB) permeability, although this phenomenon is not well characterized.

Objective: To determine the effect of SPG stimulation on the BBB using rat models.

Methods: Extravasation of fluorescent tracer 70 kDa FITC-dextran into rat brain specimens was measured across a range of stimulation parameters to assess BBB permeability. Tight junction (TJ) morphology was compared by assessing differences in the staining of proteins occludin and ZO-1 and analyzing ultrastructural changes on transmission electron microscopy (TEM) between stimulated and unstimulated specimens.

Results: SPG stimulation at 10 Hz maximally increased BBB permeability, exhibiting a 6-fold increase in fluorescent traceruptake (1.66% vs 0.28%, p < 0.0001). This effect was reversed 4-hours after stimulation (0.36% uptake, p = 0.99). High-frequency stimulation at 20 Hz and 200 Hz did not increase tracer extravasation, (0.26% and 0.28% uptake, p = >0.999 and p = 0.998, respectively). Stimulation was associated a significant decrease in the colocalization of occludin and ZO-1 with endothelial markers in stimulated brains compared to control (74.6% vs. 39.7% and 67.2% vs. 60.4% colocalization, respectively, p < 0.0001), and ultrastructural changes in TJ morphology associated with increased BBB permeability were observed on TEM.

Conclusion: This study is the first to show a reversible, frequency-dependent increase in BBB permeability with SPG stimulation and introduces a putative mechanism of action through TJ disruption. Bypassing the BBB with SPG stimulation could enable new paradigms in delivering therapeutics to the CNS. Further study of this technology is needed.

Keywords: Blood-brain barrier; Neuromodulation; Sphenopalatine ganglion; Tight junction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Electric Stimulation / methods
  • Female
  • Occludin / metabolism
  • Permeability / drug effects
  • Pterygopalatine Fossa / innervation*
  • Pterygopalatine Fossa / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Tight Junction Proteins / metabolism
  • Tight Junctions / drug effects
  • Zonula Occludens-1 Protein / metabolism


  • Occludin
  • Tight Junction Proteins
  • Zonula Occludens-1 Protein