A Novel Na +-K +-Cl - Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke

Stroke. 2019 Apr;50(4):1021-1025. doi: 10.1161/STROKEAHA.118.024287.

Abstract

Background and Purpose- Inhibition of brain NKCC1 (Na+-K+-Cl- cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.

Keywords: angiotensin II; bumetanide; hypertension; middle cerebral artery; prodrug.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / pathology
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Recovery of Function / drug effects*
  • Rotarod Performance Test
  • Sodium Potassium Chloride Symporter Inhibitors / pharmacology
  • Sodium Potassium Chloride Symporter Inhibitors / therapeutic use*
  • Solute Carrier Family 12, Member 2*
  • Stroke / drug therapy*
  • Stroke / pathology
  • Treatment Outcome

Substances

  • Sodium Potassium Chloride Symporter Inhibitors
  • Solute Carrier Family 12, Member 2