NKCC Inhibitors for Neuroprotection Following a Stroke

Stroke is the second leading cause of death and the leading cause of disability worldwide. Even where advanced technology and facilities are available, 60 percent of those who suffer a stroke die or suffer other outcomes like loss of mobility, impaired speech, or cognitive disabilities. The irreversible harm caused by interrupting blood flow to the brain unfolds hours to days after the initial blockage, so it is critical to identify early interventions that could reduce neuronal death. Several studies have suggested that upregulated Na+-K+-Cl- cotransporter (NKCC) activity in the brain plays a direct role in stroke-related cell death, which has led to interest in the NKCC blocker bumetanide. Although bumetanide has shown promise in animal models of stroke, its potent diuretic action and poor passage through the blood-brain barrier present significant limitations for its use in humans. Our novel class of NKCC1 inhibitors address bumetanide’s shortcomings to provide a safer and more effective early stroke intervention.

Description

To overcome the limitations of bumetanide as a stroke treatment, researchers have developed lipophilic and uncharged bumetanide derivatives that penetrate the blood–brain barrier more easily. Changes to the structure of the bumetanide molecule could also curb diuresis by conferring greater selectivity for NKCC1, which is primarily expressed in the brain, over NKCC2 in the kidney. In a mouse model of stroke, one of the new compounds, STS66, was more effective than bumetanide at reducing cell death, swelling, and neurological deficits in the weeks after the ischemic event. The mice receiving STS66 even lived longer.

Applications

· Treatment and prevention of stroke
· Disorders related to NKCC dysfunction

Advantages

· More effective than bumetanide
· Reduced diuretic activity, avoiding the danger of hypokalemic alkalosis
· Improved metabolic stability

Invention Readiness

In vivo data

IP Status

Abandoned - https://patents.google.com/patent/US20210163406A1

Related Publication(s)

Luo, L., Wang, J., Ding, D., Hasan, M. N., Yang, S.-S., Lin, S.-H., Schreppel, P., Sun, B., Yin, Y., Erker, T., & Sun, D. (2020). Role of NKCC1 Activity in Glioma K+ Homeostasis and Cell Growth: New Insights With the Bumetanide-Derivative STS66. Frontiers in Physiology, 11. https://doi.org/10.3389/fphys.2020.00911

Huang, H., Bhuiyan, M. I. H., Jiang, T., Song, S., Shankar, S., Taheri, T., Li, E., Schreppel, P., Hintersteininger, M., Yang, S.-S., Lin, S.-H., Molyneaux, B. J., Zhang, Z., Erker, T., & Sun, D. (2019). A Novel Na + -K + -Cl − Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke. Stroke, 50(4), 1021–1025. https://doi.org/10.1161/strokeaha.118.024287