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

Richard F. Schmidt; Thana N. Theofanis; Michael J. Lang; Geoffrey P. Stricsek; Ruihe Lin; Aurore Lebrun; D. Craig Hooper; Robert H. Rosenwasser; Ashwini D. Sharan; Lorraine Iacovitti

doi:10.1016/j.brainres.2019.04.030

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

Richard F. Schmidt, Thana N. Theofanis^*, Michael J. Lang, Geoffrey P. Stricsek, Ruihe Lin, Aurore Lebrun, D. Craig Hooper, Robert H. Rosenwasser, Ashwini D. Sharan, Lorraine Iacovitti

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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 < 0.0001). 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.

Original language	English (US)
Pages (from-to)	231-241
Number of pages	11
Journal	Brain research
Volume	1718
DOIs	https://doi.org/10.1016/j.brainres.2019.04.030
State	Published - Sep 1 2019
Externally published	Yes

Keywords

Blood-brain barrier
Neuromodulation
Sphenopalatine ganglion
Tight junction

ASJC Scopus subject areas

Neuroscience(all)
Molecular Biology
Clinical Neurology
Developmental Biology

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10.1016/j.brainres.2019.04.030

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@article{f6a1742d53244805a3a0eef2abee4c54,

title = "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 < 0.0001). 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",

author = "Schmidt, {Richard F.} and Theofanis, {Thana N.} and Lang, {Michael J.} and Stricsek, {Geoffrey P.} and Ruihe Lin and Aurore Lebrun and Hooper, {D. Craig} and Rosenwasser, {Robert H.} and Sharan, {Ashwini D.} and Lorraine Iacovitti",

note = "Funding Information: This work was supported by the Mary E. Groff Charitable Trust, who did not have a role in collection, analysis, or interpretation of data, nor the writing and submission of this manuscript. This work was also supported by the institutional funding provided by the Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University . There were no financial conflicts of interest associated with this publication. Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = sep,

day = "1",

doi = "10.1016/j.brainres.2019.04.030",

language = "English (US)",

volume = "1718",

pages = "231--241",

journal = "Brain research",

issn = "0006-8993",

publisher = "Elsevier",

}

TY - JOUR

T1 - Sphenopalatine ganglion stimulation is a reversible and frequency-dependent modulator of the blood-brain barrier

AU - Schmidt, Richard F.

AU - Theofanis, Thana N.

AU - Lang, Michael J.

AU - Stricsek, Geoffrey P.

AU - Lin, Ruihe

AU - Lebrun, Aurore

AU - Hooper, D. Craig

AU - Rosenwasser, Robert H.

AU - Sharan, Ashwini D.

AU - Iacovitti, Lorraine

N1 - Funding Information: This work was supported by the Mary E. Groff Charitable Trust, who did not have a role in collection, analysis, or interpretation of data, nor the writing and submission of this manuscript. This work was also supported by the institutional funding provided by the Vickie and Jack Farber Institute for Neuroscience at Thomas Jefferson University . There were no financial conflicts of interest associated with this publication. Publisher Copyright: © 2019

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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 < 0.0001). 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.

AB - 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 < 0.0001). 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.

KW - Blood-brain barrier

KW - Neuromodulation

KW - Sphenopalatine ganglion

KW - Tight junction

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DO - 10.1016/j.brainres.2019.04.030

M3 - Article

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AN - SCOPUS:85065816832

SN - 0006-8993

VL - 1718

SP - 231

EP - 241

JO - Brain research

JF - Brain research

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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