Veterans Affairs

SPAK Kinase inhibitor improves neurological function after ischemic stroke

Pharmacological modulator of brain salt and water homeostasis provide a non-surgical alternative to current treatments

Medical & Biotechnology

Image: Idrewfedd under CCL

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.

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