Description:
Stroke is the second leading cause of death and the leading cause of disability worldwide. 60 percent of those who suffer a stroke die or become dependent. The irrevocable harm caused by interrupting blood flow to the brain unfolds hours to days after the initial blockage, therefore, 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.
The novel class of NKCC1 inhibitors address bumetanide’s short-comings to provide a safer and more effective early stroke intervention. Scientists at the University of Vienna and the University of Pittsburgh 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:
- Disorders related to NKCC dysfunction
- Treatment or prevention of stroke
Patent protection applied for.