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A Preclinical Model to Assess Brain Recovery After Acute Stroke in Rats
Published on: November 6, 2019
Inhibition of WNK3 Kinase Signaling Reduces Brain Damage and Accelerates Neurological Recovery After Stroke
Gulnaz Begum1, Hui Yuan1, Kristopher T Kahle1
1Department of Neurology, University of Pittsburgh, Pittsburgh, PA, (G.B., H.Y., L.L., S.W., Y.S., D.S.); Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (K.T.K.); Manton Center for Orphan Diseases, Harvard Medical School, MA (K.T.K.); Renal Division and Vascular Biology Center, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA (B.E.S., S.L.A); Division of Nephrology, Dept. of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (SS.Y., SH.L); Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA (D.S).
The WNK3-SPAK/OSR1-NKCC1 pathway drives ischemic brain damage. Inhibiting this pathway protects against stroke injury, suggesting it as a therapeutic target for neuroprotection.
Area of Science:
- Molecular signaling pathways
- Neuroscience
- Cation-chloride cotransporter regulation
Background:
- WNK kinases (WNK3) and downstream SPAK/OSR1 kinases regulate cation-chloride cotransporters.
- Ischemia stimulates NKCC1, contributing to stroke pathophysiology.
- The WNK3-SPAK/OSR1 pathway's role in ischemic stroke is currently unknown.
Purpose of the Study:
- Investigate the WNK3-SPAK/OSR1 pathway as a regulator of NKCC1.
- Determine the pathway's role in ischemic brain damage and neuroprotection.
Main Methods:
- Transient middle cerebral artery occlusion in WNK3 knockout and wild-type mice.
- Assessment of infarct volume, edema, BBB damage, demyelination, and neurological deficits.
- In vitro ischemia studies using oxygen-glucose deprivation in cultured neurons and oligodendrocytes.
Main Results:
- WNK3 knockout mice showed reduced infarct volume, edema, demyelination, and improved neurological recovery.
- Neuroprotection correlated with decreased SPAK/OSR1 and NKCC1 phosphorylation and reduced NKCC1 cell surface expression.
- Genetic WNK3 inhibition or SPAK/OSR1 knockdown enhanced neuronal and oligodendrocyte tolerance to in vitro ischemia.
Conclusions:
- The WNK3-SPAK/OSR1-NKCC1 pathway is implicated in ischemic neuroglial injury.
- Targeting the WNK3-SPAK/OSR1 kinase pathway offers a potential therapeutic strategy for stroke neuroprotection.
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