Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery

Karissa E. Cottier, Emily A. Galloway, Elisa C. Calabrese, Margaret E Tome, Erika Liktor-Busa, John Kim, Thomas P Davis, Todd W Vanderah, Tally M. Largent-Milnes

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to headache. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the blood-brain barrier (BBB) may partially account for this disparity. It is known, however, that BBB permeability is increased during several CNS pathologies. In this study, we investigated BBB changes in response to KCl-induced CSD events and subsequent allodynia in rats. Cortical KCl injection in awake, freely moving rats produced facial allodynia with peak intensity between 1.5 and 3 h and CSD induction within 0.5-2 h postinjection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 h post-KCl injection and resolving within 6 h; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pretreatment with topiramate to inhibit CSD did not prevent the increased BBB paracellular permeability. CNS delivery of the abortive anti-migraine agent sumatriptan was increased in the cortex 1.5 h post-KCl injection. Surprisingly, sumatriptan uptake was also increased in the brainstem following CSD induction, suggesting regulation of active transport mechanisms at the BBB. Together, these results demonstrate the ability of CSD events to produce transient, time-dependent changes in BBB permeability when allodynia is present and to mediate access of clinically relevant therapeutics (i.e., sumatriptan) to the CNS.

Original languageEnglish (US)
JournaleNeuro
Volume5
Issue number4
DOIs
StatePublished - Jul 1 2018

Fingerprint

Cortical Spreading Depression
Blood-Brain Barrier
Headache
Sumatriptan
Permeability
Hyperalgesia
Pharmaceutical Preparations
Headache Disorders
Injections
Brain Stem
Claudin-5
Occludin
Tight Junction Proteins
Active Biological Transport
Migraine Disorders
Sucrose
Perfusion
Pathology
Brain

Keywords

  • blood-brain barrier
  • CNS
  • cortical spreading depression
  • drug delivery
  • headache
  • triptan

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cottier, K. E., Galloway, E. A., Calabrese, E. C., Tome, M. E., Liktor-Busa, E., Kim, J., ... Largent-Milnes, T. M. (2018). Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery. eNeuro, 5(4). https://doi.org/10.1523/ENEURO.0116-18.2018

Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery. / Cottier, Karissa E.; Galloway, Emily A.; Calabrese, Elisa C.; Tome, Margaret E; Liktor-Busa, Erika; Kim, John; Davis, Thomas P; Vanderah, Todd W; Largent-Milnes, Tally M.

In: eNeuro, Vol. 5, No. 4, 01.07.2018.

Research output: Contribution to journalArticle

Cottier, Karissa E. ; Galloway, Emily A. ; Calabrese, Elisa C. ; Tome, Margaret E ; Liktor-Busa, Erika ; Kim, John ; Davis, Thomas P ; Vanderah, Todd W ; Largent-Milnes, Tally M. / Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery. In: eNeuro. 2018 ; Vol. 5, No. 4.
@article{fde930b9146e452d9b0544939de81329,
title = "Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery",
abstract = "Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to headache. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the blood-brain barrier (BBB) may partially account for this disparity. It is known, however, that BBB permeability is increased during several CNS pathologies. In this study, we investigated BBB changes in response to KCl-induced CSD events and subsequent allodynia in rats. Cortical KCl injection in awake, freely moving rats produced facial allodynia with peak intensity between 1.5 and 3 h and CSD induction within 0.5-2 h postinjection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 h post-KCl injection and resolving within 6 h; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pretreatment with topiramate to inhibit CSD did not prevent the increased BBB paracellular permeability. CNS delivery of the abortive anti-migraine agent sumatriptan was increased in the cortex 1.5 h post-KCl injection. Surprisingly, sumatriptan uptake was also increased in the brainstem following CSD induction, suggesting regulation of active transport mechanisms at the BBB. Together, these results demonstrate the ability of CSD events to produce transient, time-dependent changes in BBB permeability when allodynia is present and to mediate access of clinically relevant therapeutics (i.e., sumatriptan) to the CNS.",
keywords = "blood-brain barrier, CNS, cortical spreading depression, drug delivery, headache, triptan",
author = "Cottier, {Karissa E.} and Galloway, {Emily A.} and Calabrese, {Elisa C.} and Tome, {Margaret E} and Erika Liktor-Busa and John Kim and Davis, {Thomas P} and Vanderah, {Todd W} and Largent-Milnes, {Tally M.}",
year = "2018",
month = "7",
day = "1",
doi = "10.1523/ENEURO.0116-18.2018",
language = "English (US)",
volume = "5",
journal = "eNeuro",
issn = "2373-2822",
publisher = "Society for Neuroscience",
number = "4",

}

TY - JOUR

T1 - Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery

AU - Cottier, Karissa E.

AU - Galloway, Emily A.

AU - Calabrese, Elisa C.

AU - Tome, Margaret E

AU - Liktor-Busa, Erika

AU - Kim, John

AU - Davis, Thomas P

AU - Vanderah, Todd W

AU - Largent-Milnes, Tally M.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to headache. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the blood-brain barrier (BBB) may partially account for this disparity. It is known, however, that BBB permeability is increased during several CNS pathologies. In this study, we investigated BBB changes in response to KCl-induced CSD events and subsequent allodynia in rats. Cortical KCl injection in awake, freely moving rats produced facial allodynia with peak intensity between 1.5 and 3 h and CSD induction within 0.5-2 h postinjection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 h post-KCl injection and resolving within 6 h; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pretreatment with topiramate to inhibit CSD did not prevent the increased BBB paracellular permeability. CNS delivery of the abortive anti-migraine agent sumatriptan was increased in the cortex 1.5 h post-KCl injection. Surprisingly, sumatriptan uptake was also increased in the brainstem following CSD induction, suggesting regulation of active transport mechanisms at the BBB. Together, these results demonstrate the ability of CSD events to produce transient, time-dependent changes in BBB permeability when allodynia is present and to mediate access of clinically relevant therapeutics (i.e., sumatriptan) to the CNS.

AB - Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to headache. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the blood-brain barrier (BBB) may partially account for this disparity. It is known, however, that BBB permeability is increased during several CNS pathologies. In this study, we investigated BBB changes in response to KCl-induced CSD events and subsequent allodynia in rats. Cortical KCl injection in awake, freely moving rats produced facial allodynia with peak intensity between 1.5 and 3 h and CSD induction within 0.5-2 h postinjection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 h post-KCl injection and resolving within 6 h; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pretreatment with topiramate to inhibit CSD did not prevent the increased BBB paracellular permeability. CNS delivery of the abortive anti-migraine agent sumatriptan was increased in the cortex 1.5 h post-KCl injection. Surprisingly, sumatriptan uptake was also increased in the brainstem following CSD induction, suggesting regulation of active transport mechanisms at the BBB. Together, these results demonstrate the ability of CSD events to produce transient, time-dependent changes in BBB permeability when allodynia is present and to mediate access of clinically relevant therapeutics (i.e., sumatriptan) to the CNS.

KW - blood-brain barrier

KW - CNS

KW - cortical spreading depression

KW - drug delivery

KW - headache

KW - triptan

UR - http://www.scopus.com/inward/record.url?scp=85060372785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060372785&partnerID=8YFLogxK

U2 - 10.1523/ENEURO.0116-18.2018

DO - 10.1523/ENEURO.0116-18.2018

M3 - Article

VL - 5

JO - eNeuro

JF - eNeuro

SN - 2373-2822

IS - 4

ER -