@article {CottierENEURO.0116-18.2018, author = {Karissa E. Cottier and Emily A. Galloway and Elisa C. Calabrese and Margaret E. Tome and Erika Liktor-Busa and John Kim and Thomas P. Davis and Todd W. Vanderah and Tally M. Largent-Milnes}, title = {Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery}, elocation-id = {ENEURO.0116-18.2018}, year = {2018}, doi = {10.1523/ENEURO.0116-18.2018}, publisher = {Society for Neuroscience}, 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 hours and CSD induction within 0.5 to 2 hours post-injection. Brain perfusion of 14C-sucrose as a marker of BBB paracellular permeability revealed increased leak in the cortex, but not brainstem, beginning 0.5 hours post-KCl injection and resolving within 6 hours; no changes in tight junction (TJ) proteins occludin or claudin-5 expression were observed. Acute pre-treatment 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 hours 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.Significance Statement The need to overcome the BBB is one of the major hurdles in designing CNS active drugs. CNS mechanisms have been shown to play a vital role in primary and secondary headache disorders. In this study we show that BBB permeability is transiently increased in a rat model of CSD induced episodic headache. We also observed a significant increase in sumatriptan uptake into the brain. Clinically, sumatriptan has been shown to be most efficacious when given close to the onset of headache pain, corresponding to times where we observed increased CNS uptake in our rat model. These data suggest that altered BBB permeability occurs during CSD and may be taken advantage of during therapeutic intervention.}, URL = {https://www.eneuro.org/content/early/2018/07/05/ENEURO.0116-18.2018}, eprint = {https://www.eneuro.org/content/early/2018/07/05/ENEURO.0116-18.2018.full.pdf}, journal = {eNeuro} }