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.

No abstract

26Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis 27 including fluctuations of pH occurs during cortical spreading depression (CSD) events associated 28 with several neurological disorders, including migraine with aura, traumatic brain injury and stroke.29 NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was 30 to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) 31 integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using 32 immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the 33 paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In 34 contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine 35 therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total 36 expression of NHE1 in cortex and PAG with limited impact on trigeminal ganglia or trigeminal 37 nucleus caudalis suggesting in vitro observations may have a significance in vivo. Pharmacological 38 inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early 39 time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of 40 NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the 41 antimigraine agent, sumatriptan. 3 43 Introduction 44 The Headache Classification Committee of the International Headache Society defined migraine as a 45 recurrent headache characterized by unilateral location, pulsating quality, and moderate to severe 46 intensity, which is accompanied with nausea and/or photo-phonophobia [1,2]. In approximately one 47 third of migraine patients, episodes are associated with unilateral, fully reversible, visual, sensory or 48 other CNS symptoms that usually develop gradually [3]; this symptomology is collectively termed 49 migraine aura [4]. Several clinical and neuroimaging findings support a pathophysiological 50 connection between cortical spreading depression (CSD) and migraine aura [5][6][7]. In addition to 51 migraine with aura, CSD can be induced by traumatic brain injury, hemorrhage or ischemia, and can 52 develop over the course of epileptic seizure [8]. CSD is an intense self-propagating depolarization 53 wave originated from cerebral gray matter that propagates slowly across the brain (2-5 mm/min) [9] 54 that is followed by a longer lasting wave of hyperpolarization characterized by massive flux in ionic 55 concentrations and limited neurotransmitter release [10]. CSD events can cause a triphasic 56 perturbation of extracellular pH, manifested as a small initial acidic shift, followed by a rapid 57 transient alkaline shift then a large and prolonged tissue acidosis which is coupled to neuronal but not 58 astrocytic swelling and decreases in intracellular pH [11][12][13][14]. MRI study on a case...