Pharmacological tools to target NKCC1 in brain disorders

• Published in: Trends in pharmacological sciences (Regular ed.) 2021-12, Vol.42 (12), p.1009-1034
• Main Authors: Savardi, Annalisa, Borgogno, Marco, De Vivo, Marco, Cancedda, Laura
• Format: Article
• Language: English
• Subjects: Brain Diseases - drug therapy; brain disorders; bumetanide; Bumetanide - pharmacology; Bumetanide - therapeutic use; chloride homeostasis; Chlorides - metabolism; Humans; Nervous System Diseases - drug therapy; NKCC1; selective NKCC1 inhibitors; Sodium Potassium Chloride Symporter Inhibitors - pharmacology; Sodium Potassium Chloride Symporter Inhibitors - therapeutic use; Solute Carrier Family 12, Member 2 - metabolism
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2021.09.005

The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders. A growing number of studies indicate a defective ratio of the chloride importer NKCC1 and the chloride exporter KCC2, and consequent impaired Cl intracellular regulation, in several brain conditions, from neurodevelopmental to neurological and neurodegenerative disorders.The FDA-approved diuretic bumetanide, a nonselective inhibitor of NKCC1, reverses core symptoms of several neurological disorders in rodent models and/or in clinical trials in patients.Bumetanide has low brain penetration, and its repurposing in neurological disorders brings several collateral issues and limitations due to excessive diuresis caused by NKCC2 inhibition in the kidney.Recent drug discovery efforts have evaluated novel NKCC1 inhibitors and modulators designed with diverse strategies to avoid the adverse effects of bumetanide.