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

TitleLoss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery.
Publication TypeJournal Article
Year of Publication2018
AuthorsCottier KE, Galloway EA, Calabrese EC, Tome ME, Liktor-Busa E, Kim J, Davis TP, Vanderah TW, Largent-Milnes TM
Date Published2018 Jul-Aug
KeywordsAnimals, Blood-Brain Barrier, Brain Stem, Central Nervous System Agents, Cerebral Cortex, Cortical Spreading Depression, Disease Models, Animal, Female, Headache, Hyperalgesia, Potassium Chloride, Rats, Rats, Sprague-Dawley, Sumatriptan, Topiramate

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 C-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.

Alternate JournaleNeuro
PubMed ID30073201
PubMed Central IDPMC6071204
Grant ListR01 NS099292 / NS / NINDS NIH HHS / United States
R01 DA011271 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Thomas P Davis, PhD
Erika Liktor-Busa, PhD, PharmD
Tally Largent-Milnes, PhD
Todd Vanderah, PhD