Na+-K+-2Cl- cotransport inhibitor attenuates cerebral edema following experimental stroke via the perivascular pool of aquaporin-4

Elton R. Migliati, Mahmood Amiry-Moghaddam, Stanley C. Froehner, Marvin E. Adams, Ole Petter Ottersen, Anish Bhardwaj

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Introduction: The Na+-K+-2Cl- cotransporter localized in the brain vascular endothelium has been shown to be important in the evolution of cerebral edema following experimental stroke. Previous in vivo studies have demonstrated that bumetanide, a selective Na +-K+-2Cl- cotransport inhibitor, attenuates ischemia-evoked cerebral edema. Recently, bumetanide has been shown to also inhibit water permeability via aquaporin-4 (AQP4) expressed in Xenopus laevis oocytes. We tested the hypothesis that the perivascular pool of AQP4 plays a significant role in the anti-edema effect of bumetanide by utilizing wild-type (WT) mice as well as mice with targeted disruption of α-syntrophin (α-Syn-/-) that lack the perivascular pool of AQP4. Methods: Isoflurane-anesthetized adult male WT C57Bl6 and α-Syn-/- mice were subjected to 90 min middle cerebral artery occlusion (MCAO) followed by 24 or 48 h of reperfusion. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios), and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments. Results: Bumetanide significantly attenuated infarct volume and decreased ipsilateral hemispheric water content in WT mice compared to vehicle treatment. In α-Syn-/- mice, bumetanide treatment had no effect on infarct volume or ischemia-evoked cerebral edema. Bumetanide-treated WT mice had a significant attenuation of AQP4 protein expression at 48 h post-MCAO compared to vehicle-treated WT mice. Conclusions: These data suggest that bumetanide exerts its neuroprotective and anti-edema effects partly via blockade of the perivascular pool of AQP4 and may have therapeutic potential for ischemic stroke in the clinical setting.

Original languageEnglish (US)
Pages (from-to)123-131
Number of pages9
JournalNeurocritical Care
Volume13
Issue number1
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

Aquaporin 4
Bumetanide
Brain Edema
Stroke
Middle Cerebral Artery Infarction
Reperfusion
Edema
Ischemia
Parietal Lobe
Laser-Doppler Flowmetry
Water
Isoflurane
Vascular Endothelium
Xenopus laevis
Immunoblotting
Oocytes
Permeability
Staining and Labeling
Brain

Keywords

  • Aquaporins
  • Bumetanide
  • Cerebral edema
  • Focal cerebral ischemia
  • Infarct
  • Stroke

ASJC Scopus subject areas

  • Clinical Neurology
  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

Na+-K+-2Cl- cotransport inhibitor attenuates cerebral edema following experimental stroke via the perivascular pool of aquaporin-4. / Migliati, Elton R.; Amiry-Moghaddam, Mahmood; Froehner, Stanley C.; Adams, Marvin E.; Ottersen, Ole Petter; Bhardwaj, Anish.

In: Neurocritical Care, Vol. 13, No. 1, 08.2010, p. 123-131.

Research output: Contribution to journalArticle

Migliati, Elton R. ; Amiry-Moghaddam, Mahmood ; Froehner, Stanley C. ; Adams, Marvin E. ; Ottersen, Ole Petter ; Bhardwaj, Anish. / Na+-K+-2Cl- cotransport inhibitor attenuates cerebral edema following experimental stroke via the perivascular pool of aquaporin-4. In: Neurocritical Care. 2010 ; Vol. 13, No. 1. pp. 123-131.
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abstract = "Introduction: The Na+-K+-2Cl- cotransporter localized in the brain vascular endothelium has been shown to be important in the evolution of cerebral edema following experimental stroke. Previous in vivo studies have demonstrated that bumetanide, a selective Na +-K+-2Cl- cotransport inhibitor, attenuates ischemia-evoked cerebral edema. Recently, bumetanide has been shown to also inhibit water permeability via aquaporin-4 (AQP4) expressed in Xenopus laevis oocytes. We tested the hypothesis that the perivascular pool of AQP4 plays a significant role in the anti-edema effect of bumetanide by utilizing wild-type (WT) mice as well as mice with targeted disruption of α-syntrophin (α-Syn-/-) that lack the perivascular pool of AQP4. Methods: Isoflurane-anesthetized adult male WT C57Bl6 and α-Syn-/- mice were subjected to 90 min middle cerebral artery occlusion (MCAO) followed by 24 or 48 h of reperfusion. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios), and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments. Results: Bumetanide significantly attenuated infarct volume and decreased ipsilateral hemispheric water content in WT mice compared to vehicle treatment. In α-Syn-/- mice, bumetanide treatment had no effect on infarct volume or ischemia-evoked cerebral edema. Bumetanide-treated WT mice had a significant attenuation of AQP4 protein expression at 48 h post-MCAO compared to vehicle-treated WT mice. Conclusions: These data suggest that bumetanide exerts its neuroprotective and anti-edema effects partly via blockade of the perivascular pool of AQP4 and may have therapeutic potential for ischemic stroke in the clinical setting.",
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T1 - Na+-K+-2Cl- cotransport inhibitor attenuates cerebral edema following experimental stroke via the perivascular pool of aquaporin-4

AU - Migliati, Elton R.

AU - Amiry-Moghaddam, Mahmood

AU - Froehner, Stanley C.

AU - Adams, Marvin E.

AU - Ottersen, Ole Petter

AU - Bhardwaj, Anish

PY - 2010/8

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N2 - Introduction: The Na+-K+-2Cl- cotransporter localized in the brain vascular endothelium has been shown to be important in the evolution of cerebral edema following experimental stroke. Previous in vivo studies have demonstrated that bumetanide, a selective Na +-K+-2Cl- cotransport inhibitor, attenuates ischemia-evoked cerebral edema. Recently, bumetanide has been shown to also inhibit water permeability via aquaporin-4 (AQP4) expressed in Xenopus laevis oocytes. We tested the hypothesis that the perivascular pool of AQP4 plays a significant role in the anti-edema effect of bumetanide by utilizing wild-type (WT) mice as well as mice with targeted disruption of α-syntrophin (α-Syn-/-) that lack the perivascular pool of AQP4. Methods: Isoflurane-anesthetized adult male WT C57Bl6 and α-Syn-/- mice were subjected to 90 min middle cerebral artery occlusion (MCAO) followed by 24 or 48 h of reperfusion. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios), and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments. Results: Bumetanide significantly attenuated infarct volume and decreased ipsilateral hemispheric water content in WT mice compared to vehicle treatment. In α-Syn-/- mice, bumetanide treatment had no effect on infarct volume or ischemia-evoked cerebral edema. Bumetanide-treated WT mice had a significant attenuation of AQP4 protein expression at 48 h post-MCAO compared to vehicle-treated WT mice. Conclusions: These data suggest that bumetanide exerts its neuroprotective and anti-edema effects partly via blockade of the perivascular pool of AQP4 and may have therapeutic potential for ischemic stroke in the clinical setting.

AB - Introduction: The Na+-K+-2Cl- cotransporter localized in the brain vascular endothelium has been shown to be important in the evolution of cerebral edema following experimental stroke. Previous in vivo studies have demonstrated that bumetanide, a selective Na +-K+-2Cl- cotransport inhibitor, attenuates ischemia-evoked cerebral edema. Recently, bumetanide has been shown to also inhibit water permeability via aquaporin-4 (AQP4) expressed in Xenopus laevis oocytes. We tested the hypothesis that the perivascular pool of AQP4 plays a significant role in the anti-edema effect of bumetanide by utilizing wild-type (WT) mice as well as mice with targeted disruption of α-syntrophin (α-Syn-/-) that lack the perivascular pool of AQP4. Methods: Isoflurane-anesthetized adult male WT C57Bl6 and α-Syn-/- mice were subjected to 90 min middle cerebral artery occlusion (MCAO) followed by 24 or 48 h of reperfusion. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios), and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments. Results: Bumetanide significantly attenuated infarct volume and decreased ipsilateral hemispheric water content in WT mice compared to vehicle treatment. In α-Syn-/- mice, bumetanide treatment had no effect on infarct volume or ischemia-evoked cerebral edema. Bumetanide-treated WT mice had a significant attenuation of AQP4 protein expression at 48 h post-MCAO compared to vehicle-treated WT mice. Conclusions: These data suggest that bumetanide exerts its neuroprotective and anti-edema effects partly via blockade of the perivascular pool of AQP4 and may have therapeutic potential for ischemic stroke in the clinical setting.

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