Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake.

TitleFunctional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake.
Publication TypeJournal Article
Year of Publication2020
AuthorsLiktor-Busa E, Blawn KT, Kellohen KL, Wiese BM, Verkhovsky V, Wahl J, Vivek A, Palomino SM, Davis TP, Vanderah TW, Largent-Milnes TM
JournalPLoS One
Date Published2020
KeywordsAnimals, Blood-Brain Barrier, Brain, Central Nervous System, Cortical Spreading Depression, Disease Models, Animal, Endothelial Cells, Female, Gene Expression Regulation, Humans, Injections, Intraperitoneal, Migraine with Aura, Rats, Sodium-Hydrogen Exchanger 1, Sumatriptan, Trigeminal Ganglion

Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG but increased expression in trigeminal ganglia; no changes were seen in trigeminal nucleus caudalis. Thus, in vitro observations may have a significance in vivo to increase brain sumatriptan levels. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.

Alternate JournalPLoS One
PubMed ID32469979
PubMed Central IDPMC7259629
Grant ListR01 NS099292 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Thomas P Davis, PhD
Erika Liktor-Busa, PhD, PharmD
Tally Largent-Milnes, PhD
Todd Vanderah, PhD