Premium
Effects of novel NKCC1 inhibitors on reducing brain damage and neurological deficits after ischemic stroke in mice
Author(s) -
HUANG HUACHEN,
Bhuiyan Mohammad Iqbal Hossain,
Jiang Tong,
Shankar Sandhya,
Schreppel Philipp,
Erker Thomas,
Hintersteininger Michael,
Sun Dandan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.824.2
Subject(s) - medicine , stroke (engine) , edema , pharmacology , anesthesia , brain damage , mechanical engineering , engineering
Background and Purpose Stimulation of the WNK‐SPAK/OSR1 kinases and their substrate Na + ‐K + ‐2Cl − cotransporter 1 (NKCC1) play critical roles in cerebral edema and neurological functional deficits after ischemic stroke. Either NKCC1 inhibitor bumetanide (BMT) or knockout of WNK3 or SPAK shows profound protective effects in a mouse model of ischemic stroke. In this study, we investigated the efficacy of two novel pharmacological inhibitors of NKCC1, a lipophilic BMT prodrug STS5 and a novel NKCC1 inhibitor STS66, on reducing ischemic stroke‐induced brain damage in mouse. Methods Both male and female C57BL/6j mice (2–3 months old) were used in this study. Transiant focal ischemic stroke was induced by 50‐min occlusion of the middle cerebral artery (tMCAO). At 3 h post‐tMCAO, mice were randomly assigned to receive vehicle DMSO (2 ml/kg body weight/day, i.p.), BMT (10 mg/kg/day, i.p.), STS5 (13 mg/kg, i.p.), or STS66 (12 mg/kg/day, i.p.). Infarct volume, hemisphere swelling, animal survival, and neurological deficits were analyzed. Results BMT, STS5 or STS66 significantly reduced infarct volume and hemisphere swelling assessed at 24 h post‐tMCAO. STS66 is less effective on reducing brain infaraction in female than in male mice. However, STS5 treatment significantly increased the mortality in mice during 1–14 days after tMCAO. Interestingly, STS66‐treated mice showed better outcome, including improving survival and sensorimotor functional recovery during 1–14 days post‐tMCAO. Conclusion These results demonstrate that the novel NKCC1 inhibitor STS66 is effective in reducing ischemic infarct, cerebral swelling, and improving neurological deficits after ischemic stroke in C57BL/6j mice. STS66‐mediated NKCC1 inhibition presents a novel strategy for stroke therapy. Support or Funding Information This research was supported in part by NIH Grant R01 NS38118 (D Sun), VA I01BX002891 (D Sun) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .