The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

Park, Sung Lyea; Lee, Dong Ha; Yoo, Sung‐Eun

doi:10.1016/j.brainres.2010.09.077

Cited by 20 publications

(9 citation statements)

References 30 publications

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“…Recently, NHE1 inhibition was reported as a viable strategy to alleviate BBB injury induced by stroke and subarachnoid hemorrhage in animal models [26][27][28][29]45]. We asked if functional expression of NHE1 is critical to maintaining paracellular integrity of the BBB using an in vitro model.…”

Section: Functional Nhe1 Is Required For Intact Paracellular Bbb Intementioning

confidence: 99%

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

et al. 2020

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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.

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Section: Functional Nhe1 Is Required For Intact Paracellular Bbb Intementioning

confidence: 99%

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

et al. 2020

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“…Blocking NHE1 activity with sabiporide significantly alleviates ischemia/aglycemic hypoxia-induced leakage of Evans Blue dye, showing protection against BBB hyperpermeability. Sabiporide also reduced the ischemia-induced disruption of the tight junction proteins occludin and zonula (Park et al, 2010). Given the broad expression of NHE1 in different cell types of the neurovascular unit, the protective effects of NHE1 inhibition on BBB damage in vivo may result from its effects on EC or indirect effects from surrounding parenchymal cells.…”

Section: The Sodium/hydrogen Exchangersmentioning

confidence: 99%

Proton-sensitive cation channels and ion exchangers in ischemic brain injury: New therapeutic targets for stroke?

Leng¹,

Shi²,

Xiong³

et al. 2014

Progress in Neurobiology

104

101

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Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na+/H+ exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H+-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca2+, Na+, and Zn2+, and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre-clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention.

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“…Another study reported that pharmacological inhibition of NHE‐1 by sabiporide prevented ischemia‐induced increase in blood–brain barrier (BBB) permeability by preventing disruption of tight junction proteins in vivo as well as in an endothelial cell culture model (Park et al. ). More recently, it was reported that astrocytic NHE‐1 contributes to neurovascular injury after ischemic stroke and knock‐out of NHE‐1 selectively in astrocytes reduces BBB permeability and reactive astrogliosis after stroke (Begum et al.…”

Section: Discussionmentioning

confidence: 99%

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

Ward

Dong

et al. 2019

Physiol Rep

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Experimental studies have demonstrated protective effects of NHE ‐1 inhibition on cardiac function; however, clinical trials utilizing NHE ‐1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase‐derived reactive oxygen species ( ROS ) from microglial cells have been shown to contribute to injury following stroke. We have recently demonstrated that NHE ‐1 inhibition enhances ROS in macrophages in a Hv1‐dependent manner. As Hv1 protein is highly expressed in microglia, we hypothesized that “ NHE ‐1 inhibition may augment neurovascular injury by activating Hv1,” providing a potential mechanism for the deleterious effects of NHE ‐1. The goal of this study was to determine whether neurovascular injury and functional outcomes after experimental stroke differed in wild‐type and Hv1 mutant Dahl salt‐sensitive rats treated with an NHE ‐1 inhibitor. Stroke was induced using both transient and permanent of middle cerebral artery occlusion ( MCAO ). Animals received vehicle or NHE ‐1 inhibitor KR 32568 (2 mg/kg, iv) either 30 min after the start of MCAO or were pretreated (2 mg/kg, iv, day) for 3 days and then subjected to MCAO . Our data indicate that Hv1 deletion confers both neuronal and vascular protection after ischemia. In contrast to our hypothesis, inhibition of NHE ‐1 provided further protection from ischemic stroke, and the beneficial effects of both pre‐ and post‐treatment with KR 32568 were similar in wild‐type and Hv1 −/− rats. These data indicate that Hv1 activation is unlikely to be responsible for the increased incidence of cerebrovascular events observed in the heart disease patients after NHE ‐1 inhibition treatment.

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The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

Cited by 20 publications

References 30 publications

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

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

Proton-sensitive cation channels and ion exchangers in ischemic brain injury: New therapeutic targets for stroke?

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

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The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

Cited by 20 publications

References 30 publications

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

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

Proton-sensitive cation channels and ion exchangers in ischemic brain injury: New therapeutic targets for stroke?

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na + /H + exchanger‐1 antagonism

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Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism