Sphenopalatine Ganglion Stimulation is a Reversible and Frequency-Dependent Modulator of the Blood-Brain Barrier

Abstract 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 tracer uptake (1.66% vs 0.28%, 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  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.