Scientists at the U.S. Department of Veterans Affairs (VA) have recently developed therapeutic which may prove effective against the brain damage caused by stroke. The patented technology is available via patent license agreement to companies that would make, use, or sell it commercially.
Ischemic stroke is typically caused by a blood clot in the brain and can cause brain death within minutes. Post-stroke, impaired cell volume levels can result in swelling of the brain, a severe and difficult to treat complication addressed by the highly invasive procedures of craniectomy or shunting of cerebral spinal fluid. What is needed are pharmacological modulators of brain salt and water homeostasis to treat the post-stroke brain and limit damage.
Na-K-Cl cotransporters (NKCCs) are proteins belonging to the cation-chloride-cotransporters (CCC) subfamily and shuttle those elements into cells. One of the two isoforms, NKCC1 is expressed in many regions of the brain. NKCC1 is controlled by a signaling pathway comprised of two kinases to control cell volume and epithelial ion transport.
VA researchers have established that WNK kinase and SPS1-related proline/alanine-rich kinase (SPAK) inhibition prevents the activation of NKCC1 and reduces cerebral injury following ischemic stroke. Inhibition of this kinase activity protects neurons and oligodendrocytes against injury and death.
Further, the VA researchers have developed a compound targeting the above pathway to be used as a therapeutic in stroke patients. This dual CCC modulator (NKCC I inhibitor/KCC activator), 5-chloro-N-(5-chloro-4-(( 4-chlorophenyl)(cyano) methyl)-2-methyl phenyl)-2-hydroxybenzamide named ZT-la potently and selectively inhibits SPAK kinase – the CCC master regulator.
The drug, while still in the lab, shows promise in treating a wide array of hypoxic brain injuries resulting from such insults as traumatic brain injury, ischemic stroke, carbon monoxide poisoning, drowning, choking, suffocating, or cardiac arrest
Mode of action: Intracerebroventiricular delivery of ZT-1a normalizes CSF hypersecretion in hemorrhagic sygrocephalus by decreasing SPAK mediated phosphorylation of NKCC1 and KCC4 in choroid plexus. Systemic ZT-1a administration after experimental ischemic stroke attenuates cerebral infarction and edema and improves neurological outcomes.
ZT-1 a as a potent modulator of SPAK-dependent CCC phosphorylation, in contrast to the existing SPAK kinase inhibitors Closantel, STOCKI S-50699 and STOCKIS-14279, which only at 10 μM significantly inhibited phosphorylation of KCCs.
- ZT-1 a holds promise as an effective kinase-cotransporter modulator capable of restoring brain water homeostasis and improving neurological function
- WNK/SPAK/NKCC1 signaling complex is a novel, potential therapeutic target for neuroprotection and preservation of myelination following stroke
- Businesses can commercialize the technology by licensing U.S. Patent application from the VA. (Unpublished application available under NDA)
- License fees paid to the VA are negotiable
- Businesses that license the technology may have the opportunity to pursue collaborative research with the inventors
- Testing data may be available to companies evaluating the technology
- TechLink guides businesses through evaluation and licensing; services provided at no cost
- VA ID: 2018-318